Drug releasing coatings for medical devices

ABSTRACT

The invention relates to a medical device for delivering a therapeutic agent to a tissue. The medical device has a layer overlying the exterior surface of the medical device. The layer contains a therapeutic agent and an additive. The additive has a hydrophilic part and a hydrophobic part and the therapeutic agent is not enclosed in micelles or encapsulated in particles or controlled release carriers.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a divisional of application Ser. No. 11/942,452, filed Nov. 19,2007, which application claims the benefit of priority under 35 U.S.C.§119 of U.S. Provisional Application No. 60/860,084, filed on Nov. 20,2006, U.S. Provisional Application No. 60/880,742, filed Jan. 17, 2007,U.S. Provisional Application No. 60/897,427, filed on Jan. 25, 2007,U.S. Provisional Application No. 60/903,529 filed on Feb. 26, 2007, U.S.Provisional Application No. 60/926,850 filed Apr. 30, 2007, U.S.Provisional Application No. 60/904,473 filed Mar. 2, 2007, U.S.Provisional Application No. 60/981,380 filed Oct. 19, 2007, and U.S.Provisional Application 60/981,384 filed Oct. 19, 2007, the disclosuresof all of which are incorporated by reference herein.

FIELD OF THE INVENTION

Embodiments of the present invention relate to coated medical devices,and particularly to coated balloon catheters, and their use for rapidlydelivering a therapeutic agent to particular tissue or body lumen.Embodiments of the present invention also relate to methods ofmanufacturing these medical devices, the coatings provided on thesemedical devices, the solutions for making those coatings, and methodsfor treating a body lumen such as the vasculature, includingparticularly arterial vasculature, for example, using these coatedmedical devices.

BACKGROUND OF THE INVENTION

It has become increasingly common to treat a variety of medicalconditions by introducing a medical device into the vascular system orother lumen within a human or veterinary patient such as the esophagus,trachea, colon, biliary tract, or urinary tract. For example, medicaldevices used for the treatment of vascular disease include stents,catheters, balloon catheters, guide wires, cannulas and the like. Whilethese medical devices initially appear successful, the benefits areoften compromised by the occurrence of complications, such as latethrombosis, or recurrence of disease, such as stenosis (restenosis),after such treatment.

Restenosis, for example, involves a physiological response to thevascular injury caused by angioplasty. Over time, de-endotheliaziationand injury to smooth muscle cells results in thrombus deposition,leukocyte and macrophage infiltration, smooth muscle cellproliferation/migration, fibrosis and extracellular matrix deposition.Inflammation plays a pivotal role linking early vascular injury to theeventual consequence of neointimal growth and lumen compromise. Inballoon-injured arteries, leukocyte recruitment is confined to earlyneutrophil infiltration, while in stented arteries, early neutrophilrecruitment is followed by prolonged macrophage accumulation. Thewidespread use of coronary stents has altered the vascular response toinjury by causing a more intense and prolonged inflammatory state, dueto chronic irritation from the implanted foreign body, and in the caseof drug eluting stents (DES), from insufficient biocompatibility of thepolymer coating.

Over the past several years, numerous local drug delivery systems havebeen developed for the treatment and/or the prevention of restenosisafter balloon angioplasty or stenting. Examples include local drugdelivery catheters, delivery balloon catheters, and polymeric drugcoated stents. Given that many diseases affect a specific local site ororgan within the body, it is advantageous to preferentially treat onlythe affected area. This avoids high systemic drug levels, which mayresult in adverse side effects, and concentrates therapeutic agents inthe local area where they are needed. By treating just the diseasedtissue, the total quantity of drug used may be significantly reduced.Moreover, local drug delivery may allow for the use of certain effectivetherapeutic agents, which have previously been considered too toxic ornon-specific to use systemically.

One example of a local delivery system is a drug eluting stent (DES).The stent is coated with a polymer into which drug is impregnated. Whenthe stent is inserted into a blood vessel, the polymer degrades and thedrug is slowly released. The slow release of the drug, which takes placeover a period of weeks to months, has been reported as one of the mainadvantages of using DES. However, while slow release may be advantageousin the case where a foreign body, such as a stent, is deployed, which isa source of chronic irritation and inflammation, if a foreign body isnot implanted it is instead advantageous to rapidly deliver drug to thevascular tissue at the time of treatment to inhibit inflammation andcellular proliferation following acute injury. Thus, a considerabledisadvantage of a DES, or any other implanted medical device designedfor sustained release of a drug, is that the drug is incapable of beingrapidly released into the vessel.

Additionally, while drug-eluting stents were initially shown to be aneffective technique for reducing and preventing restenosis, recentlytheir efficacy and safety have been questioned. A life-threateningcomplication of the technology, late thrombosis, has emerged as a majorconcern. Drug eluting stents cause substantial impairment of arterialhealing, characterized by a lack of complete re-endothelialization and apersistence of fibrin when compared to bare metal stents (BMS), which isunderstood to be the underlying the cause of late DES thrombosis.Concerns have also been raised that the polymeric matrix on the stent inwhich the anti-proliferative drug is embedded might exacerbateinflammation and thrombosis, since the polymers used are notsufficiently biocompatible. These polymeric systems are designed tofacilitate long-term sustained release of drug over a period of days,months, or years, not over a period of seconds or minutes. Rapid releaseof drug, an intent of embodiments of the present invention, from thesepolymeric systems is not possible. Thus, combining a therapeutic agentwith a polymer in a medical device coating may have significantdisadvantages.

Another important limitation of the DES is that the water insolubledrugs are not evenly distributed in the polymeric matrix of the coating.Furthermore, drug and polymer are concentrated on the struts of thestent, but not in gaps between the struts. The non-uniform distributionof drug causes non-uniform drug release to the tissue of the vesselwalls. This may cause tissue damage and thrombosis in areas exposed toexcess drug and hyperplasia and restenosis areas that are undertreated.Thus, there is a need to improve the uniformity of drug delivery totarget tissues by improving drug solubility in coatings of medicaldevices by increasing the drug's compatibility with carriers in thecoatings, such as a polymeric matrix, thereby eliminating or reducingthe size of drug crystal particles in the polymeric matrix or othercoating to create a uniform drug distribution in the drug coating on themedical device.

Yet another important limitation of the DES is that only a limitedamount of an active agent can be loaded into the relatively smallsurface area of the stent.

Non-stent based local delivery systems, such as balloon catheters, havealso been effective in the treatment and prevention of restenosis. Theballoon is coated with an active agent, and when the blood vessel isdilated, the balloon is pressed against the vessel wall to deliver theactive agent. Thus, when balloon catheters are used, it is advantageousfor the drug in the coating to be rapidly released and absorbed by bloodvessel tissues. Any component of the coating that inhibits rapidrelease, such as a lipid or polymer or an encapsulating particle, isnecessarily disadvantageous to the intended use of the balloon catheter,which is inflated for a very brief period of time and then removed fromthe body.

Hydrophilic drugs, such as heparin, have been reported to be deliverableby polymeric hydrogel coated balloon catheters. However, a polymerichydrogel coating can not effectively deliver water insoluble drugs (suchas paclitaxel and rapamycin), because they can not mix with the hydrogelcoating.

The iodine contrast agent iopromide has been used with paclitaxel tocoat balloon catheters and has some success in treatment of restenosis.It was reported that contrast agent improves adhesion of paclitaxel tothe balloon surface. Iodinated contrast agents suffer from several wellknown disadvantages. When used for diagnostic procedures, they may havecomplication rates of 5-30%. These agents are associated with the riskof bradycardia, ventricular arrthymia, hypotension, heart block, sinusarrest, sinus tachycardia, and fibrillation. Iodine contrast agents mayalso induce renal failure, and as a result there are significant effortsto remove these contrast agents from the vascular system afterdiagnostic procedures.

Iodinated X-ray contrast agents are large hydrophilic sphericalmolecules. They are characterized by an extracellular distribution andrapid glomerular filtration and renal excretion. They are unable tocross membrane lipid bilayers to enter cells of the vasculature becausethey are large, polar, hydrophilic molecules. They are therefore notoptimally effective at carrying hydrophobic drugs such as paclitaxelinto cells, and the percent of paclitaxel reported to be taken up byvascular tissue after deployment of these devices is only 5-20%.

Alternatively, balloon catheters are reported to have been coated withhydrophobic therapeutic agents that have been mixed with oils or lipidsor encapsulated in particles such as liposomes or polymers. All of thesedrug delivery formulations have significant disadvantages. Unlikehydrophilic contrast agents, oils and lipids mix well withwater-insoluble drugs such as paclitaxel or rapamycin, but the particlesizes of oils used for solubilizing the therapeutic agents arerelatively unstable, ranging in a broad particle size distribution fromseveral hundred nanometers to several microns in diameter.

Loading capacity of conventional micelles is low. Another disadvantageof oil-based liposome formulations is the dependence of drug absorptionon the rate and extent of lipolysis. Lipolysis of oil-basedtriglycerides is difficult and dependent upon many factors, andtriglycerides must be digested and drug released in order to be absorbedby diseased tissue. The amount of hydrophobic drug delivered to tissuesby these agents will be low, because liposomes and micelles cannotefficiently release hydrophobic drug, which they carry away before itcan be absorbed by tissues. Oils and lipids are therefore not effectiveat rapidly and efficiently facilitating tissue uptake of drug during avery brief device deployment time, and no report has shown these typesof coatings to be effective.

Drug that is encapsulated in polymeric particles may take even longer todiffuse from the coating and will have further difficulty permeatingtarget tissues rapidly. Microspheres formed with polymeric materials,such as polyesters, when used to encapsulate water insoluble drugs, areunable to release the drug until the polymeric material is degraded.Thus, these polymeric microspheres are useful for sustained release ofdrug over a long period of time but cannot rapidly release drug andfacilitate tissue uptake.

Combining drugs and medical devices is a complicated area of technology.It involves the usual formulation challenges, such as those of oral orinjectable pharmaceuticals, together with the added challenge ofmaintaining drug adherence to the medical device until it reaches thetarget site and subsequently delivering the drug to the target tissueswith the desired release and absorption kinetics. Drug coatings ofmedical devices must also have properties such that they do not crackupon expansion and contraction of the device, for example, of a ballooncatheter or a stent. Furthermore, coatings must not impair functionalperformance such as burst pressure and compliance of balloons or theradial strength of self- or balloon-expanded stents. The coatingthickness must also be kept to a minimum, since a thick coating wouldincrease the medical device's profile and lead to poor trackability anddeliverability. These coatings generally contain almost no liquidchemicals, which typically are often used to stabilize drugs. Thus,formulations that are effective with pills or injectables might not workat all with coatings of medical device. If the drug releases from thedevice too easily, it may be lost during device delivery before it canbe deployed at the target site. If the drug adheres too strongly, thedevice may be withdrawn before the drug can be released and absorbed bytissues at the target tissues.

Thus, there is still a need to develop highly specialized coatings formedical devices that can rapidly deliver therapeutic agents, drugs, orbioactive materials directly into a localized tissue area during orfollowing a medical procedure, so as to treat or prevent vascular andnonvascular diseases such as restenosis. The device should quicklyrelease the therapeutic agent in an effective and efficient manner atthe desired target location, where the therapeutic agent should rapidlypermeate the target tissue.

SUMMARY OF THE INVENTION

The present inventor has found that coating the exterior surface of amedical device, and particularly of a balloon catheter or a stent, forexample, with a layer comprising a therapeutic agent and an additivethat has both a hydrophilic part and a hydrophobic part is useful insolving the problems associated with the coatings discussed above.Surprisingly, the present inventor has found that the at least oneadditive according to embodiments of the present invention, whichcomprises a hydrophilic part and a hydrophobic part, in combination witha therapeutic agent, forms an effective drug delivery coating on amedical device without the use of oils and lipids, thereby avoiding thelipolysis dependence and other disadvantages of conventional oil-basedcoating formulations. Moreover, the additives according to embodimentsof the present invention facilitate rapid drug elution and superiorpermeation of drug into tissues at a disease site. Thus, coatingsaccording to embodiments of the present invention provide an enhancedrate and/or extent of absorption of the hydrophobic therapeutic agent indiseased tissues of the vasculature or other body lumen.

In one embodiment, the present invention relates to a medical device fordelivering a therapeutic agent to a tissue, the device comprising alayer overlying an exterior surface of the medical device. The deviceincludes one of a balloon catheter, a perfusion balloon catheter, acutting balloon catheter, a scoring balloon catheter, a laser catheter,an atherectomy device, a debulking catheter, a stent, a filter, a stentgraft, a covered stent, a patch, a wire, and a valve. Further, thetissue includes tissue of one of coronary vasculature, peripheralvasculature, cerebral vasculature, esophagus, airways, sinus, trachea,colon, biliary tract, urinary tract, prostate, and brain passages.

In one embodiment of the medical device, the layer overlying theexterior surface of the medical device comprises a therapeutic agent andan additive, wherein the additive comprises a hydrophilic part and ahydrophobic part, wherein the therapeutic agent is not enclosed inmicelles or encapsulated in polymer particles, and wherein the layerdoes not include an iodine covalent bonded contrast agent. In oneembodiment, the layer overlying the exterior surface of the medicaldevice consists essentially of the therapeutic agent and the additive.

In one embodiment, the layer overlying the exterior surface of themedical device does not include oil, a lipid, or a polymer. In anotherembodiment, the layer overlying the exterior surface of the medicaldevice does not include oil. In another embodiment, the layer overlyingthe exterior surface of the medical device does not include a polymer.In another embodiment, the layer overlying the exterior surface of themedical device does not include a purely hydrophobic additive. Inanother embodiment, the layer overlying the exterior surface of themedical device does not include a dye. In another embodiment, the layeroverlying the exterior surface of the medical device does not includesalicylic acid or salts thereof. In yet another this embodiment, thelayer overlying the exterior surface of the medical device does notinclude sodium salicylate.

In one embodiment, the additive in the layer comprising the therapeuticagent and the additive is an ionic or non-ionic surfactant. In anotherembodiment, the additive is a vitamin or derivative thereof. In anotherembodiment, the additive is an amino acid or derivative thereof. Inanother embodiment, the additive is a protein or derivative thereof. Inanother embodiment, the additive is an albumin. In another embodiment,the additive is soluble in an aqueous solvent and is soluble in anorganic solvent. In another embodiment, the additive is an organic acidor an anhydride thereof. In yet another embodiment, the additive ischosen from sorbitan oleate and sorbitan fatty esters.

In one embodiment, the additive in the layer comprising the therapeuticagent and the additive is chosen from PEG fatty esters and alcohols,glycerol fatty esters, sorbitan fatty esters, PEG glyceryl fatty esters,PEG sorbitan fatty esters, sugar fatty esters, PEG sugar esters,vitamins and derivatives, amino acids, multi amino acids andderivatives, peptides, polypeptides, proteins, quaternary ammoniumsalts, organic acids, salts and anhydrides. In another embodiment, theadditive in the layer comprising the therapeutic agent and the additiveis chosen from chemical compounds having multiple hydroxyl, amino,carbonyl, carboxyl, or ester moieties.

In another embodiment, the additive in the layer comprising thetherapeutic agent and the additive is chosen fromp-isononylphenoxypolyglycidol, PEG laurate, PEG oleate, PEG stearate,PEG glyceryl laurate, PEG glyceryl oleate, PEG glyceryl stearate,polyglyceryl laurate, plyglyceryl oleate, polyglyceryl myristate,polyglyceryl palmitate, polyglyceryl-6 laurate, plyglyceryl-6 oleate,polyglyceryl-6 myristate, polyglyceryl-6 palmitate, polyglyceryl-10laurate, plyglyceryl-10 oleate, polyglyceryl-10 myristate,polyglyceryl-10 palmitate, PEG sorbitan monolaurate, PEG sorbitanmonolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, PEG oleylether, PEG laurayl ether, octoxynol, monoxynol, tyloxapol, sucrosemonopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside,n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside,heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside,n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside,nonanoyl-N-methylglucamide, n-noyl-β-D-glucopyranoside,octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside,octyl-β-D-thioglucopyranoside; cystine, tyrosine, tryptophan, leucine,isoleucine, phenylalanine, asparagine, aspartic acid, glutamic acid, andmethionine (amino acids); acetic anhydride, benzoic anhydride, ascorbicacid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone carboxylate,ethylenediaminetetraacetic dianhydride, maleic and anhydride, succinicanhydride, diglycolic anhydride, glutaric anhydride, acetiamine,benfotiamine, pantothenic acid (organic acids and anhydrides);cetotiamine; cyclothiamine, dexpanthenol, niacinamide, nicotinic acid,pyridoxal 5-phosphate, nicotinamide ascorbate, riboflavin, riboflavinphosphate, thiamine, folic acid, menadiol diphosphate, menadione sodiumbisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6,and vitamin U (vitamins); albumin, immunoglobulins, caseins,hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin, fibronectins,vitronectins, firbinogens, lipases (proteins), benzalkonium chloride,benzethonium chloride, docecyl trimethyl ammonium bromide, sodiumdocecylsulfates, dialkyl methylbenzyl ammonium chloride, anddialkylesters of sodium sulfonsuccinic acid (ionic surfactants),L-ascorbic acid and its salt, D-glucoascorbic acid and its salt,tromethamine, glucamine, glucoheptonic acid, glucomic acid,gluconolactone, glucosamine, glutamic acid (chemical compounds withmultiple hydroxyl, amino, carbonyl, carboxyl, or ester moieties).

In another embodiment, the additive in the layer comprising thetherapeutic agent and the additive is chosen from Tyloxapol, Octoxynol,oleth, laureth, PEG-glyceryl, monolaurate, PEG-20 monolaurate, PEG 20monooleate, PEG 20 glyceryl monooleate, Nonoxynol,Nonylphenylpoly(glycidol), Octyl-betha-D-glycopyranoside, anddeconoyl-N-methylglucamide.

In another embodiment, the additive in the layer comprising thetherapeutic agent and the additive is chosen from benzalkonium chloride,benzethonium chloride, docecyl trimethyl ammonium bromide, sodiumdocecylsulfates, dialkyl methylbenzyl ammonium chloride, anddialkylesters of sodium sulfonsuccinic acid.

In one embodiment, the therapeutic agent in the layer comprising thetherapeutic agent and the additive is one of paclitaxel and analoguesthereof, rapamycin and analogues thereof, beta-lapachone and analoguesthereof, biological vitamin D and analogues thereof, and a mixture ofthese therapeutic agents. In another embodiment, the therapeutic agentis in combination with a second therapeutic agent, wherein thetherapeutic agent is one of paclitaxel, rapamycin, and analoguesthereof, and wherein the second therapeutic agent is one ofbeta-lapachone, biological active vitamin D and their analogues. In oneembodiment, the therapeutic agent is not water soluble.

In one embodiment, the additive enhances penetration and absorption ofthe therapeutic agent in tissue. In another embodiment, the additivepenetrates tissue, and the therapeutic agent is not water soluble. Inanother embodiment, the additive has a water and ethanol solubility ofat least 1 mg/ml and the therapeutic agent is not water soluble.

In one embodiment, the concentration of the additive in the layer isfrom 1 to 10 μg/mm². In one embodiment, the concentration of thetherapeutic agent in the layer is from 1 to 20 μg/mm². In anotherembodiment, the concentration of the therapeutic agent in the layer isfrom 2 to 6 μg/mm².

In one embodiment of the medical device, the device is capable ofdelivering the therapeutic agent to the tissue in about 0.2 to 2minutes. In another embodiment, the device is capable of delivering thetherapeutic agent to the tissue in about 0.1 to 1 minute.

In one embodiment, the medical device comprising a layer overlying anexterior surface of the medical device further comprises an adherentlayer between the exterior surface of the medical device and the layer.In another embodiment, the device further comprises a top layeroverlying the surface of the layer to prevent loss of drug duringtransit through a body to the tissue. In another embodiment, the medicaldevice further comprises a dimethylsulfoxide solvent layer, wherein thedimethylsulfoxide solvent layer is overlying the surface of the layer.

In another embodiment of the medical device, the layer overlying theexterior surface of the medical device comprises a therapeutic agent andat least two additives, wherein each of the additives comprises ahydrophilic part and a hydrophobic part and wherein each additive issoluble in polar organic solvent and is soluble in water, and whereinthe therapeutic agent is not enclosed in micelles or encapsulated inpolymer particles. In one aspect of this embodiment, the polar organicsolvent is selected from methanol, ethanol, isopropanol, acetone,dimethylformide, tetrahydrofuran, methylethyl ketone, dimethylsulfoxide,acetonitrile, ethyl acetate, and chloroform and mixtures of these polarorganic solvents with water.

In another embodiment of the medical device, the layer overlying theexterior surface of the medical device comprises a therapeutic agent andan additive, wherein the additive comprises a hydrophilic part and ahydrophobic part, wherein the additive reduces crystal size and numberof particles of the therapeutic agent, and wherein the therapeutic agentis not water soluble and is not enclosed in micelles or encapsulated inpolymer particles.

In another embodiment of the medical device, the layer overlying theexterior surface of the medical device comprises a therapeutic agent andan additive, wherein the additive comprises a hydrophilic part and ahydrophobic part, wherein the additive has a fatty chain of an acid,ester, ether, or alcohol, wherein the fatty chain directly inserts intolipid membrane structures of tissue, wherein the therapeutic agent isnot water soluble and is not enclosed in micelles or encapsulated inpolymer particles, and wherein the layer does not include an iodinecovalent bonded contrast agent.

In another embodiment of the medical device, the layer overlying theexterior surface of the medical device comprises a therapeutic agent andan additive, wherein the additive comprises a hydrophilic part and ahydrophobic part, wherein the additive penetrates into and rearrangeslipid membrane structures of the tissue, and wherein the therapeuticagent is not water soluble and is not enclosed in micelles orencapsulated in polymer particles.

In another embodiment of the medical device, the layer overlying theexterior surface of the medical device comprises a therapeutic agent andan additive, wherein the additive comprises a hydrophilic part and ahydrophobic part, wherein the additive is a surfactant and has a fattychain of an acid, ester, ether, or alcohol, wherein the fatty chaindirectly inserts into the lipid membrane structures of the tissue,wherein the therapeutic agent is not water soluble and is not enclosedin micelles or encapsulated in polymer particles, and wherein the layerdoes not include an iodine covalent bonded contrast agent.

In another embodiment of the medical device, the layer overlying theexterior surface of the medical device comprises a therapeutic agent andan additive, wherein the additive comprises a hydrophilic part and ahydrophobic part, wherein the additive has more than four hydroxyl,carboxyl, or amine groups as components of the hydrophilic part, whereinthe therapeutic agent is not water soluble and is not enclosed inmicelles or encapsulated in polymer particles, and wherein the layerdoes not include an iodine covalent bonded contrast agent.

In yet another embodiment, the present invention relates to a stentcoating for delivering a therapeutic agent to a tissue, the stentcoating comprising a layer overlying a surface of the stent. In oneaspect of this embodiment, the layer overlying the surface of the stentcomprises a therapeutic agent, an additive, and a polymer matrix,wherein the therapeutic agent is dispersed, but not encapsulated, asparticles in the polymer matrix, wherein the additive comprises ahydrophilic part and a hydrophobic part, wherein the additive improvesthe compatibility of the therapeutic agent and the polymer matrix, andwherein the additive reduces the particle sizes and improves uniformityof distribution of the therapeutic agent in the polymer matrix.

In yet another embodiment, the present invention relates to a medicaldevice for delivering a drug to a tissue that is prepared from amixture. In one aspect of this embodiment, the mixture comprises anorganic phase containing drug particles dispersed therein and an aqueousphase containing a water soluble additive, wherein the additive is notan iodine covalent bonded contrast agent or a dye. In another aspect ofthis embodiment, the preparation mixture includes homogenization underhigh shear conditions and optionally under pressure. In another aspectof this embodiment, the water soluble additive is selected from albumin,polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidinone,polypeptides, water soluble surfactants, water soluble vitamins, andproteins.

In another embodiment, the present invention relates to a ballooncatheter for delivering a therapeutic agent to a blood vessel, thecatheter comprising a coating layer overlying an exterior surface of aballoon. In one embodiment of the balloon catheter, the coating layercomprises a therapeutic agent and an additive, wherein the additivecomprises a hydrophilic part and a hydrophobic part, and wherein thetherapeutic agent is not enclosed in micelles or encapsulated in polymerparticles, and wherein the layer does not include an iodine covalentbonded contrast agent. In one aspect of this embodiment, the coatinglayer overlying an exterior surface of the exterior surface of themedical device consists essentially of the therapeutic agent and theadditive.

In one embodiment of the balloon catheter, the additive in the coatinglayer is an ionic or non-ionic surfactant. In another embodiment, theadditive is a vitamin or derivative thereof. In another embodiment, theadditive is an amino acid or derivative thereof. In another embodiment,the additive is a protein or derivative thereof. In another embodiment,the additive is a albumin. In another embodiment, the additive issoluble in an aqueous solvent and is soluble in an organic solvent. Inanother embodiment, the additive is an organic acid or an anhydridethereof. In yet another embodiment, the additive is chosen from sorbitanoleate and sorbitan fatty esters.

In one embodiment of the balloon catheter, the coating layer overlyingthe exterior surface of the balloon does not include a purelyhydrophobic additive. In another embodiment, the coating layer overlyingthe exterior surface of the balloon does not contain a dye. In anotherembodiment, the coating layer overlying the exterior surface of theballoon does not include salicylic acid or salts thereof. In anotherembodiment, the coating layer overlying the surface of the balloon doesnot include sodium salicylate. In another embodiment, the coating layeroverlying the surface of the balloon does not include oil, a lipid, or apolymer. In yet another embodiment, the coating layer overlying thesurface of the balloon does not include oil. In another aspect of thisembodiment, the coating layer does not include a polymer.

In one embodiment, the additive in the coating layer comprising thetherapeutic agent and the additive is chosen from PEG fatty esters andalcohols, glycerol fatty esters, sorbitan fatty esters, PEG glycerylfatty esters, PEG sorbitan fatty esters, sugar fatty esters, PEG sugaresters, vitamins and derivatives, amino acids, multi amino acids andderivatives, peptides, polypeptides, proteins, quaternary ammoniumsalts, organic acids, salts and anhydrides.

In another embodiment, the additive in the coating layer comprising thetherapeutic agent and the additive is chosen fromp-isononylphenoxypolyglycidol, PEG laurate, PEG oleate, PEG stearate,PEG glyceryl laurate, PEG glyceryl oleate, PEG glyceryl stearate,polyglyceryl laurate, plyglyceryl oleate, polyglyceryl myristate,polyglyceryl palmitate, polyglyceryl-6 laurate, plyglyceryl-6 oleate,polyglyceryl-6 myristate, polyglyceryl-6 palmitate, polyglyceryl-10laurate, plyglyceryl-10 oleate, polyglyceryl-10 myristate,polyglyceryl-10 palmitate PEG sorbitan monolaurate, PEG sorbitanmonolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, PEG oleylether, PEG laurayl ether, octoxynol, monoxynol, tyloxapol, sucrosemonopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside,n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside,heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside,n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside,nonanoyl-N-methylglucamide, n-noyl-β-D-glucopyranoside,octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside,octyl-β-D-thioglucopyranoside; cystine, tyrosine, tryptophan, leucine,isoleucine, phenylalanine, asparagine, aspartic acid, glutamic acid, andmethionine (amino acids); acetic anhydride, benzoic anhydride, ascorbicacid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone carboxylate,ethylenediaminetetraacetic dianhydride, maleic and anhydride, succinicanhydride, diglycolic anhydride, glutaric anhydride, acetiamine,benfotiamine, pantothenic acid (organic acids and anhydrides);cetotiamine; cyclothiamine, dexpanthenol, niacinamide, nicotinic acid,pyridoxal 5-phosphate, nicotinamide ascorbate, riboflavin, riboflavinphosphate, thiamine, folic acid, menadiol diphosphate, menadione sodiumbisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6,and vitamin U (vitamins); albumin, immunoglobulins, caseins,hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin, fibronectins,vitronectins, firbinogens, lipases (proteins), benzalkonium chloride,benzethonium chloride, docecyl trimethyl ammonium bromide, sodiumdocecylsulfates, dialkyl methylbenzyl ammonium chloride, anddialkylesters of sodium sulfonsuccinic acid (ionic surfactants),L-ascorbic acid and its salt, D-glucoascorbic acid and its salt,tromethamine, glucamine, glucoheptonic acid, glucomic acid,gluconolactone, glucosamine, glutamic acid (chemical compounds withmultiple hydroxyl, amino, carbonyl, carboxyl, or ester moieties).

In another embodiment, the additive in the coating layer comprising thetherapeutic agent and the additive is chosen from Tyloxapol, Octoxynol,oleth, laureth, PEG-glyceryl, monolaurate, PEG-20 monolaurate, PEG 20monooleate, PEG 20 glyceryl monooleate, Nonoxynol,Nonylphenylpoly(glycidol), Octyl-betha-D-glycopyranoside, anddeconoyl-N-methylglucamide.

In another embodiment, the additive in the coating layer comprising thetherapeutic agent and the additive is chosen from benzalkonium chloride,benzethonium chloride, docecyl trimethyl ammonium bromide, sodiumdocecylsulfates, dialkyl methylbenzyl ammonium chloride, anddialkylesters of sodium sulfonsuccinic acid.

In one embodiment, the therapeutic agent is one of paclitaxel andanalogues thereof, rapamycin and analogues thereof, beta-lapachone andanalogues thereof, biological vitamin D and analogues thereof, and amixture of these therapeutic agents. In another embodiment, thetherapeutic agent is in combination with a second therapeutic agent,wherein the therapeutic agent is one of paclitaxel, rapamycin, andanalogues thereof, and wherein the second therapeutic agent is one ofbeta-lapachone, biological active vitamin D and their analogues. In oneembodiment, the therapeutic agent is not water soluble.

In one embodiment, the additive enhances penetration and absorption ofthe therapeutic agent in the blood vessel. In another embodiment, theadditive penetrates the blood vessel, and the therapeutic agent is notwater soluble. In another embodiment, the additive has a water andethanol solubility of at least 1 mg/ml, and the therapeutic agent is notwater soluble.

In one embodiment of the balloon catheter, the catheter furthercomprises an adherent layer between the exterior surface of the balloonand the coating layer. In another embodiment, the catheter furthercomprises a top layer overlying the coating layer, wherein the top layerprevents loss of the therapeutic agent during transit through a body tothe blood vessel. In another embodiment, the catheter further comprisesa dimethylsulfoxide solvent layer, wherein the dimethylsulfoxide solventlayer is overlying the surface of the coating layer.

In one embodiment, the balloon catheter is capable of delivering thetherapeutic agent to the blood vessel in about 0.2 to 2 minutes. Inanother embodiment, the balloon catheter is capable of delivering thetherapeutic agent to the blood vessel in about 0.1 to 1 minute.

In one embodiment of the balloon catheter, the concentration of thetherapeutic agent in the coating layer is from 1 to 20 μg/mm². Inanother embodiment, the concentration of the therapeutic agent in thecoating layer is from 2 to 6 μg/mm². In one embodiment, theconcentration of the additive in the coating layer is from 1 to 10μg/mm².

In yet a further embodiment, the present invention relates to a ballooncatheter for delivering a therapeutic agent to a blood vessel. In oneaspect of this embodiment, the catheter comprises an elongate memberhaving a lumen and a distal end, an expandable balloon attached to thedistal end of the elongate member and in fluid communication with thelumen, and a coating layer overlying an exterior surface of the balloon.In one aspect of this embodiment, the coating layer overlying thesurface of the balloon comprises a therapeutic agent and an additive,wherein the additive comprises a hydrophilic part and a hydrophobicpart, wherein the therapeutic agent is not enclosed in micelles orencapsulated in particles or delayed release carriers, wherein the layerdoes not include oil, a lipid, a polymer, or an iodine covalent bondedcontrast agent, and wherein the catheter is capable of delivering thetherapeutic agent to the blood vessel in less than about 2 minutes. Inone aspect of this embodiment, the layer does not include a purelyhydrophobic additive. In another aspect of this embodiment, the layerdoes not contain a dye. In yet another aspect of this embodiment, theadditive is a polypeptide or protein.

In one embodiment, the coating layer overlying the surface of theballoon consists essentially of the therapeutic agent and the additive.

In one embodiment, the therapeutic agent in the coating layer overlyingthe surface of the balloon is paclitaxel and analogues thereof. Inanother embodiment, the therapeutic agent in the coating layer overlyingthe surface of the balloon is rapamycin and analogues thereof.

In one embodiment, the concentration of the therapeutic agent in thecoating layer is from 2.5 to 6 μg/mm².

In one embodiment, the additive in the coating layer overlying thesurface of the balloon is an ionic or non-ionic surfactant. In anotherembodiment, the additive in the coating layer overlying the surface ofthe balloon is a vitamin or derivative thereof.

In one embodiment, the additive in the coating layer overlying thesurface of the balloon is chosen from Tyloxapol, Octoxynol, oleth,laureth, PEG-glyceryl, monolaurate, PEG-20 monolaurate, PEG 20monooleate, PEG 20 glyceryl monooleate, Nonoxynol,Nonylphenylpoly(glycidol), Octyl-betha-D-glycopyranoside, anddeconoyl-N-methylglucamide. In another embodiment, the additive in thecoating layer overlying the surface of the balloon is chosen from PEGfatty esters and alcohols, glycerol fatty esters, sorbitan fatty esters,PEG glyceryl fatty esters, PEG sorbitan fatty esters, sugar fattyesters, PEG sugar esters, vitamins and derivatives, amino acids, multiamino acids and derivatives, peptides, polypeptides, proteins,quaternary ammonium salts, organic acids, salts and anhydrides.

In another embodiment, the additive in the coating layer overlying thesurface of the balloon is chosen from p-isononylphenoxypolyglycidol, PEGlaurate, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG glyceryloleate, PEG glyceryl stearate, polyglyceryl laurate, plyglyceryl oleate,polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate,plyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, polyglyceryl-10 laurate, plyglyceryl-10 oleate,polyglyceryl-10 myristate, polyglyceryl-10 palmitate PEG sorbitanmonolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEGsorbitan stearate, PEG oleyl ether, PEG laurayl ether, octoxynol,monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside; cystine,tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine,aspartic acid, glutamic acid, and methionine (amino acids); aceticanhydride, benzoic anhydride, ascorbic acid, 2-pyrrolidone-5-carboxylicacid, sodium pyrrolidone carboxylate, ethylenediaminetetraaceticdianhydride, maleic and anhydride, succinic anhydride, diglycolicanhydride, glutaric anhydride, acetiamine, benfotiamine, pantothenicacid (organic acids and anhydrides); cetotiamine; cyclothiamine,dexpanthenol, niacinamide, nicotinic acid, pyridoxal 5-phosphate,nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine,folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU (vitamins); albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases, benzalkonium chloride, benzethonium chloride,docecyl trimethyl ammonium bromide, sodium docecylsulfates, dialkylmethylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid (ionic surfactants), L-ascorbic acid and its salt,D-glucoascorbic acid and its salt, tromethamine, glucamine,glucoheptonic acid, glucomic acid, gluconolactone, glucosamine, glutamicacid, polyglycidol, glycerols and multiglycerols (chemical compoundswith multiple hydroxyl, amino, carbonyl, carboxyl, or ester moieties).In yet another embodiment, the additive in the coating layer overlyingthe surface of the balloon is chosen from benzalkonium chloride,benzethonium chloride, docecyl trimethyl ammonium bromide, sodiumdocecylsulfates, dialkyl methylbenzyl ammonium chloride, anddialkylesters of sodium sulfonsuccinic acid.

In one embodiment, the balloon catheter further comprises adimethylsulfoxide solvent layer overlying the coating layer, wherein thedimethylsulfoxide layer enhances the ability of the therapeutic agent topenetrate into the blood vessel. In another embodiment, the ballooncatheter further comprises an adherent layer between the exteriorsurface of the balloon and the coating layer. In yet another embodiment,the balloon catheter further comprises a top layer overlying the coatinglayer, wherein the top layer prevents loss of the therapeutic agentduring transit through a body to the blood vessel.

In yet a further embodiment, the present invention relates to apharmaceutical composition for treating a diseased body lumen or cavityafter a surgical or interventional procedure, wherein the compositioncomprises a therapeutic agent and an additive, wherein the additivecomprises a hydrophilic part and a hydrophobic part, wherein thetherapeutic agent is not enclosed in micelles or encapsulated in polymerparticles, and wherein the composition does not include an iodinecovalent bonded contrast agent.

In yet a further embodiment, the present invention relates to a methodfor treating a diseased body lumen or cavity after a surgical orinterventional procedure comprising delivering a pharmaceuticalcomposition at a surgical site by injection or spraying with a catheter,wherein the composition comprises a therapeutic agent and an additive,wherein the additive comprises a hydrophilic part and a hydrophobicpart, wherein the therapeutic agent is not enclosed in micelles orencapsulated in polymer particles, and wherein the composition does notinclude an iodine covalent bonded contrast agent.

In yet a further embodiment, the present invention relates to apharmaceutical composition for treating a cancer including cancers ofthe ovary, breast, lung, esophagus, head and neck region, bladder,brain, liver, colon and lymphomas, wherein the composition comprises atherapeutic agent and an additive, wherein the additive comprises ahydrophilic part and a hydrophobic part, wherein the therapeutic agentis not enclosed in micelles or encapsulated in polymer particles, andwherein the composition does not include an iodine covalent bondedcontrast agent. In one aspect of this embodiment, the therapeutic agentis chosen from paclitaxel and analogues thereof and rapamycin andanalogues thereof.

In yet a further embodiment, the present invention relates to a solutionfor coating a medical device. In one aspect of this embodiment, thesolution comprises an organic solvent, a therapeutic agent, and anadditive, wherein the additive comprises a hydrophilic part and ahydrophobic part, wherein the therapeutic agent is not enclosed inmicelles or encapsulated in polymer particles, and wherein the solutiondoes not include an iodine covalent bonded contrast agent. In one aspectof this embodiment, the solution does not include a purely hydrophobicadditive. In another aspect of this embodiment, the solution does notcontain a dye. In another embodiment, the solution for coating a medicaldevice does not include oil, a lipid, or a polymer.

In one embodiment, the additive in the coating solution is an ionic ornon-ionic surfactant. In another embodiment, the additive is a vitaminor derivative thereof.

In one embodiment, the additive in the coating solution is chosen fromTyloxapol, Octoxynol, oleth, laureth, PEG-glyceryl, monolaurate, PEG-20monolaurate, PEG 20 monooleate, PEG 20 glyceryl monooleate, Nonoxynol,Nonylphenylpoly(glycidol), Octyl-betha-D-glycopyranoside, anddeconoyl-N-methylglucamide.

In another embodiment, the additive in the coating solution is chosenfrom PEG fatty esters and alcohols, glycerol fatty esters, sorbitanfatty esters, PEG glyceryl fatty esters, PEG sorbitan fatty esters,sugar fatty esters, PEG sugar esters, vitamins and derivatives, aminoacids, multi amino acids and derivatives, peptides, polypeptides,proteins, quaternary ammonium salts, organic acids, salts andanhydrides.

In another embodiment, the additive in the coating solution is chosenfrom p-isononylphenoxypolyglycidol, PEG laurate, PEG oleate, PEGstearate, PEG glyceryl laurate, PEG glyceryl oleate, PEG glycerylstearate, polyglyceryl laurate, plyglyceryl oleate, polyglycerylmyristate, polyglyceryl palmitate, polyglyceryl-6 laurate, plyglyceryl-6oleate, polyglyceryl-6 myristate, polyglyceryl-6 palmitate,polyglyceryl-10 laurate, plyglyceryl-10 oleate, polyglyceryl-10myristate, polyglyceryl-10 palmitate PEG sorbitan monolaurate, PEGsorbitan monolaurate, PEG sorbitan monooleate, PEG sorbitan stearate,PEG oleyl ether, PEG laurayl ether, octoxynol, monoxynol, tyloxapol,sucrose monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside,n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside,heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside,n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside,nonanoyl-N-methylglucamide, n-noyl-β-D-glucopyranoside,octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside,octyl-β-D-thioglucopyranoside; cystine, tyrosine, tryptophan, leucine,isoleucine, phenylalanine, asparagine, aspartic acid, glutamic acid, andmethionine (amino acids); acetic anhydride, benzoic anhydride, ascorbicacid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone carboxylate,ethylenediaminetetraacetic dianhydride, maleic and anhydride, succinicanhydride, diglycolic anhydride, glutaric anhydride, acetiamine,benfotiamine, pantothenic acid (organic acids and anhydrides);cetotiamine; cyclothiamine, dexpanthenol, niacinamide, nicotinic acid,pyridoxal 5-phosphate, nicotinamide ascorbate, riboflavin, riboflavinphosphate, thiamine, folic acid, menadiol diphosphate, menadione sodiumbisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6,and vitamin U (vitamins); albumin, immunoglobulins, caseins,hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin, fibronectins,vitronectins, firbinogens, lipases (proteins), benzalkonium chloride,benzethonium chloride, docecyl trimethyl ammonium bromide, sodiumdocecylsulfates, dialkyl methylbenzyl ammonium chloride, anddialkylesters of sodium sulfonsuccinic acid (ionic surfactants),L-ascorbic acid and its salt, D-glucoascorbic acid and its salt,tromethamine, glucamine, glucoheptonic acid, glucomic acid,gluconolactone, glucosamine, glutamic acid (chemical compounds withmultiple hydroxyl, amino, carbonyl, carboxyl, or ester moieties).

In another embodiment, the additive in the solution is chosen fromsorbirtan troleate, and sorbitan fatty esters. In yet anotherembodiment, the additive in the coating solution is chosen frombenzalkonium chloride, benzethonium chloride, docecyl trimethyl ammoniumbromide, sodium docecylsulfates, dialkyl methylbenzyl ammonium chloride,and dialkylesters of sodium sulfonsuccinic acid.

In one embodiment, the therapeutic agent in the coating solution ispaclitaxel or rapamycin.

In one embodiment, the content of the therapeutic agent in the solutionis from 0.5-50% by weight. In one embodiment, the content of theadditive in the coating solution is from 1-45% by weight.

In one embodiment, the additive in the solution is soluble in aqueoussolvent and is soluble in organic solvent.

In yet a further embodiment, the present invention relates to a medicaldevice for delivering a therapeutic agent to a tissue, the devicecomprising a first layer applied to an exterior surface of the medicaldevice, and a second layer overlying the first layer. In one aspect ofthis embodiment, the first layer comprises a therapeutic agent, and thesecond layer comprises an additive, wherein the additive comprises ahydrophilic part and a hydrophobic part, and wherein the therapeuticagent in the first layer is not enclosed in micelles or encapsulated inpolymer particles. In one aspect of this embodiment, the first layerfurther comprises an additive. In another aspect of this embodiment, thesecond layer further comprises a therapeutic agent. In yet a furtheraspect of this embodiment, the first layer further comprises an additiveand the second layer further comprises a therapeutic agent.

In a further embodiment, the present invention relates to a two layercoating comprising a first layer comprising a therapeutic agent, and asecond layer comprising an additive. In one aspect of this embodiment,the second layer may be overlying the first layer. In one aspect of thisembodiment, the additive in the second layer comprises a hydrophilicpart and a hydrophobic part, and the therapeutic agent in the firstlayer is not enclosed in micelles or encapsulated in polymer particles.In one aspect of this embodiment, the first layer further comprises anadditive. In another aspect of this embodiment, the second layer furthercomprises a therapeutic agent. In yet another aspect of this embodiment,the first layer further comprises an additive and the second layerfurther comprises a therapeutic agent.

In a further embodiment, the present invention relates to a method forpreparing a medical device. In one aspect of this embodiment, the methodcomprises (a) preparing a coating solution comprising an organicsolvent, a therapeutic agent, and an additive, wherein the additivecomprises a hydrophilic part and a hydrophobic part, and wherein thetherapeutic agent is not enclosed in micelles or encapsulated in polymerparticles, and wherein the solution does not include an iodine covalentbonded contrast agent, (b) applying the coating solution to a medicaldevice, and (c) drying the coating solution, forming a coating layer. Inone aspect of this embodiment, the coating is applied by dipping aportion of the exterior surface of the medical device in the coatingsolution. In another aspect of this embodiment, the coating is appliedby spraying a portion of the exterior surface of the medical device witha coating solution. In another aspect of this embodiment, steps (b) and(c) are repeated until a therapeutically effective amount of thetherapeutic agent in the coating layer is deposited on the surface ofthe medical device. In another aspect of this embodiment, the totalthickness of the coating layer is from about 0.1 to 200 microns. Inanother aspect of this embodiment, the concentration density of the atleast one therapeutic agent applied to the surface of the medical deviceis from about 1 to 20 μg/mm², or in another aspect from about 2 to 6μg/mm². In yet another aspect of this embodiment, the method furthercomprises applying a dimethylsulfoxide solvent to the dried coatinglayer obtained in (c).

In another embodiment, the method for preparing the medical devicecomprises, (a) preparing a coating solution comprising an organicsolvent, a therapeutic agent, and an additive, wherein the additive isan anhydride, (b) applying the coating solution to a medical device, (c)drying the coating solution, forming a coating layer, and (d)hydrolyzing the anhydride to an acid group.

In a further embodiment, the present invention relates to a method forpreparing a drug coated balloon catheter. In one aspect of thisembodiment, the method comprises, (a) preparing a coating solutioncomprising an organic solvent, a therapeutic agent, and an additive,wherein the coating solution does not include an iodine covalent bondedcontrast agent or a dye, (b) applying the coating solution to aninflated balloon catheter, and (c) deflating and folding the ballooncatheter and drying the coating solution to increase uniformity of drugcoating.

In a further embodiment, the present invention relates to a method fortreating a blood vessel. In one aspect of this embodiment, the methodcomprises inserting a medical device comprising a coating layer into theblood vessel, wherein the coating layer comprises a therapeutic agentand an additive, wherein the additive comprises a hydrophilic part and ahydrophobic part, wherein the coating layer does not include an iodinecovalent contrast agent or a dye, and wherein the therapeutic agent isnot enclosed in micelles or encapsulated in polymer particles, andreleasing the therapeutic agent into the tissue of the blood vessel in 2minutes or less.

In a further embodiment, the present invention relates to a method fortreating a total occlusion of body passages. In one aspect of thisembodiment, the method comprises removing plaques in the body passagesby one of a debulking catheter, a laser atherectomy, a directingatherectomy, or a rotational atherectomy, inserting a medical devicecomprising a coating layer into the body passages, wherein the coatinglayer comprises a therapeutic agent and an additive, wherein theadditive comprises a hydrophilic part and a hydrophobic part, andwherein the coating layer does not include an iodine covalent contrastagent or a dye, and releasing the therapeutic agent into the tissue ofthe body passage or lumen, such as a blood vessel, in 2 minutes or less.

In a further embodiment, the present invention relates to a method fortreating tissue of a body comprising bringing a medical devicecomprising a coating layer into contact with tissue of the body, whereinthe coating layer comprises a therapeutic agent and an additive, whereinthe additive comprises a hydrophilic part and a hydrophobic part, andwherein the coating layer does not include an iodine covalent contrastagent or a dye, and releasing the therapeutic agent into the tissue in 2minutes or less. In one aspect of this embodiment, the tissue includestissue of one of coronary vasculature, peripheral vasculature, cerebralvasculature, esophagus, airways, sinus, trachea, colon, biliary tract,urinary tract, prostate, and brain passages.

In yet a further embodiment, the present invention relates to a processof producing a balloon catheter. In one aspect of this embodiment, theprocess comprises preparing a solution comprising an organic solvent, atherapeutic agent, and an additive, wherein the additive comprises ahydrophilic part and a hydrophobic part, and wherein the therapeuticagent is not enclosed in micelles or encapsulated in polymer particles,applying the solution to the balloon catheter, and evaporating thesolvent.

In yet a further embodiment, the present invention relates to a medicaldevice comprising a layer overlying an exterior surface of the medicaldevice, the layer comprising a therapeutic agent and an additive,wherein the additive is one of PEG fatty ester, PEG fatty ether, and PEGfatty alcohols. In one aspect of this embodiment, the additive is chosenfrom PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10laurate, PEG-10 oleate, PEG-12 laurate, PEG-12 oleate, PEG-15 oleate,PEG-20 laurate, PEG-20 oleate, PEG-20 dilaurate, PEG-20 dioleate, PEG-20distearate, PEG-32 dilaurate and PEG-32 dioleate. In another aspect ofthis embodiment, the tissue includes tissue of one of coronaryvasculature, peripheral vasculature, cerebral vasculature, esophagus,airways, sinus, trachea, colon, biliary tract, urinary tract, prostate,and brain passages. In yet another aspect of this embodiment, the deviceincludes one of a balloon catheter, a perfusion balloon catheter, acutting balloon catheter, a scoring balloon catheter, a laser catheter,an atherectomy device, a debulking catheter, a stent, a filter, a stentgraft, a covered stent, a patch, a wire, and a valve.

In yet a further embodiment, the present invention relates to a medicaldevice comprising a layer overlying an exterior surface of the medicaldevice, the layer comprising a therapeutic agent and an additive,wherein the additive is one of glycerol and polyglycerol fatty estersand PEG glycerol fatty esters. In one aspect of this embodiment, theadditive is chosen from polyglyceryl oleate, polyglyceryl-2 dioleate,polyglyceryl-10 trioleate, polyglyceryl stearate, polyglyceryl laurate,polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl linoleate,polyglyceryl-10 laurate, polyglyceryl-10 oleate, polyglyceryl-10 mono,dioleate, polyglyceryl-10 stearate, polyglyceryl-10 laurate,polyglyceryl-10 myristate, polyglyceryl-10 palmitate, polyglyceryl-10linoleate, polyglyceryl-6 stearate, polyglyceryl-6 laurate,polyglyceryl-6 myristate, polyglyceryl-6 palmitate, and polyglyceryl-6linoleate, polyglyceryl polyricinoleates, PEG-20 glyceryl laurate,PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-20 glyceryloleate, and PEG-30 glyceryl oleate. In another aspect of thisembodiment, the tissue includes tissue of one of coronary vasculature,peripheral vasculature, cerebral vasculature, esophagus, airways, sinus,trachea, colon, biliary tract, urinary tract, prostate, and brainpassages. In yet another aspect of this embodiment, the device includesone of a balloon catheter, a perfusion balloon catheter, a cuttingballoon catheter, a scoring balloon catheter, a laser catheter, anatherectomy device, a debulking catheter, a stent, a filter, a stentgraft, a covered stent, a patch, a wire, and a valve.

In yet a further embodiment, the present invention relates to a medicalcomprising a layer overlying an exterior surface of the medical device,the layer comprising a therapeutic agent and an additive, wherein theadditive is one of sorbitan fatty esters, and PEG sorbitan esters. Inone aspect of this embodiment, the additive is chosen from sorbitanmonolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitanmonostearate, PEG-20 sorbitan monolaurate, PEG-20 sorbitanmonopalmitate, PEG-20 sorbitan monooleate, and PEG-20 sorbitanmonostearate. In another aspect of this embodiment, the tissue includestissue of one of coronary vasculature, peripheral vasculature, cerebralvasculature, esophagus, airways, sinus, trachea, colon, biliary tract,urinary tract, prostate, and brain passages. In yet another aspect ofthis embodiment, the device includes one of a balloon catheter, aperfusion balloon catheter, a cutting balloon catheter, a scoringballoon catheter, a laser catheter, an atherectomy device, a debulkingcatheter, a stent, a filter, a stent graft, a covered stent, a patch, awire, and a valve.

In yet a further embodiment, the present invention relates to a medicaldevice comprising a layer overlying an exterior surface of the medicaldevice, the layer comprising a therapeutic agent and an additive,wherein the additive is a chemical compound containing a phenol moiety.In one aspect of this embodiment, the additive is chosen fromp-isononylphenoxypolyglycidol, octoxynol, monoxynol, tyloxapol,octoxynol-9, and monoxynol-9. In another aspect of this embodiment, thetissue includes tissue of one of coronary vasculature, peripheralvasculature, cerebral vasculature, esophagus, airways, sinus, trachea,colon, biliary tract, urinary tract, prostate, and brain passages. Inyet another aspect of this embodiment, the device includes one of aballoon catheter, a perfusion balloon catheter, a cutting ballooncatheter, a scoring balloon catheter, a laser catheter, an atherectomydevice, a debulking catheter, a stent, a filter, a stent graft, acovered stent, a patch, a wire, and a valve.

In yet a further embodiment, the present invention relates to a medicaldevice comprising a layer overlying an exterior surface of the medicaldevice, the layer comprising a therapeutic agent and an additive,wherein the additive is a sugar or sugar derivative. In one aspect ofthis embodiment, the additive is chosen from sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside,D-glucoascorbic acid and its salt, tromethamine, glucamine,glucoheptonic acid, glucomic acid, gluconolactone, and glucosamine. Inanother aspect of this embodiment, the tissue includes tissue of one ofcoronary vasculature, peripheral vasculature, cerebral vasculature,esophagus, airways, sinus, trachea, colon, biliary tract, urinary tract,prostate, and brain passages. In yet another aspect of this embodiment,the device includes one of a balloon catheter, a perfusion ballooncatheter, a cutting balloon catheter, a scoring balloon catheter, alaser catheter, an atherectomy device, a debulking catheter, a stent, afilter, a stent graft, a covered stent, a patch, a wire, and a valve.

In yet a further embodiment, the present invention relates to a medicaldevice comprising a layer overlying an exterior surface of the medicaldevice, the layer comprising a therapeutic agent and an additive,wherein the additive is an ionic surfactant. In one aspect of thisembodiment, the additive is chosen from benzalkonium chloride,benzethonium chloride, cetylpyridinium chloride, docecyl trimethylammonium bromide, sodium docecylsulfates, dialkyl methylbenzyl ammoniumchloride, edrophonium chloride, domiphen bromide, dialkylesters ofsodium sulfonsuccinic acid, sodium dioctyl sulfosuccinate, sodiumcholate, and sodium taurocholate. In another aspect of this embodiment,the tissue includes tissue of one of coronary vasculature, peripheralvasculature, cerebral vasculature, esophagus, airways, sinus, trachea,colon, biliary tract, urinary tract, prostate, and brain passages. Inyet another aspect of this embodiment, the device includes one of aballoon catheter, a perfusion balloon catheter, a cutting ballooncatheter, a scoring balloon catheter, a laser catheter, an atherectomydevice, a debulking catheter, a stent, a filter, a stent graft, acovered stent, a patch, a wire, and a valve.

In yet a further embodiment, the present invention relates to a medicaldevice comprising a layer overlying an exterior surface of the medicaldevice, the layer comprising a therapeutic agent and an additive,wherein the additive is a vitamin or vitamin derivative. In one aspectof this embodiment, the additive is chosen from acetiamine,benfotiamine, pantothenic acid, cetotiamine, cyclothiamine,dexpanthenol, niacinamide, nicotinic acid and its salts, pyridoxal5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate,thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, vitamin U,ergosterol, 1-alpha-hydroxycholecal-ciferol, vitamin D2, vitamin D3,alpha-carotene, beta-carotene, gamma-carotene, vitamin A, fursultiamine,methylolriboflavin, octotiamine, prosultiamine, riboflavine, vintiamol,dihydrovitamin K1, menadiol diacetate, menadiol dibutyrate, menadioldisulfate, menadiol, vitamin K1, vitamin K1 oxide, vitamins K2, andvitamin K-S(II). In another aspect of this embodiment, the tissueincludes tissue of one of coronary vasculature, peripheral vasculature,cerebral vasculature, esophagus, airways, sinus, trachea, colon, biliarytract, urinary tract, prostate, and brain passages. In yet anotheraspect of this embodiment, the device includes one of a ballooncatheter, a perfusion balloon catheter, a cutting balloon catheter, ascoring balloon catheter, a laser catheter, an atherectomy device, adebulking catheter, a stent, a filter, a stent graft, a covered stent, apatch, a wire, and a valve.

In yet a further embodiment, the present invention relates to a medicaldevice comprising a layer overlying an exterior surface of the medicaldevice, the layer comprising a therapeutic agent and an additive,wherein the additive is an amino acid, an amino acid salt, or an aminoacid derivative. In one aspect of this embodiment, the additive ischosen from alanine, arginine, asparagine, aspartic acid, cysteine,glutamic acid, glutamine, glycine, histidine, proline, isoleucine,leucine, lysine, methionine, phenylalanine, serine, threonine,tryptophan, tyrosine, valine, and their derivatives. In another aspectof this embodiment, the tissue includes tissue of one of coronaryvasculature, peripheral vasculature, cerebral vasculature, esophagus,airways, sinus, trachea, colon, biliary tract, urinary tract, prostate,and brain passages. In yet another aspect of this embodiment, the deviceincludes one of a balloon catheter, a perfusion balloon catheter, acutting balloon catheter, a scoring balloon catheter, a laser catheter,an atherectomy device, a debulking catheter, a stent, a filter, a stentgraft, a covered stent, a patch, a wire, and a valve.

In yet a further embodiment, the present invention relates to a medicaldevice for delivering a therapeutic agent to a tissue, the devicecomprising a layer overlying an exterior surface of the medical device,the layer comprising a therapeutic agent and an additive, wherein theadditive is a peptide, oligopeptide, or protein. In one aspect of thisembodiment, the additive is chosen from albumins, immunoglobulins,caseins, hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin,fibronectins, vitronectins, firbinogens, and lipases. In another aspectof this embodiment, the tissue includes tissue of one of coronaryvasculature, peripheral vasculature, cerebral vasculature, esophagus,airways, sinus, trachea, colon, biliary tract, urinary tract, prostate,and brain passages. In yet another aspect of this embodiment, the deviceincludes one of a balloon catheter, a perfusion balloon catheter, acutting balloon catheter, a scoring balloon catheter, a laser catheter,an atherectomy device, a debulking catheter, a stent, a filter, a stentgraft, a covered stent, a patch, a wire, and a valve.

In yet a further embodiment, the present invention relates to a medicaldevice for delivering a therapeutic agent to a tissue, the devicecomprising a layer overlying an exterior surface of the medical device,the layer comprising a therapeutic agent and an additive, wherein theadditive is an organic acid or an organic acid ester or anhydride. Inone aspect of this embodiment, the additive is chosen from acetic acidand anhydride, benzoic acid and anhydride, diethylenetriaminepentaaceticacid dianhydride, ethylenediaminetetraacetic dianhydride, maleic acidand anhydride, succinic acid and anhydride, diglycolic acid andanhydride, glutaric acid and anhydride, ascorbic acid, citric acid,tartaric acid, lactic acid, oxalic acid aspartic acid, nicotinic acid,and 2-pyrrolidone-5-carboxylic acid. In another aspect of thisembodiment, the tissue includes tissue of one of coronary vasculature,peripheral vasculature, cerebral vasculature, esophagus, airways, sinus,trachea, colon, biliary tract, urinary tract, prostate, and brainpassages. In yet another aspect of this embodiment, the device includesone of a balloon catheter, a perfusion balloon catheter, a cuttingballoon catheter, a scoring balloon catheter, a laser catheter, anatherectomy device, a debulking catheter, a stent, a filter, a stentgraft, a covered stent, a patch, a wire, and a valve.

It is understood that both the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of the present invention as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of an exemplary embodiment of a ballooncatheter according to the present invention.

FIGS. 2A-2C are cross-sectional views of different embodiments of thedistal portion of the balloon catheter of FIG. 1, taken along line A-A,showing exemplary coating layers.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

Embodiments of the present invention relate to medical devices,including particularly balloon catheters and stents, having a rapiddrug-releasing coating and methods for preparing such coated devices.The therapeutic agent according to embodiments of the present inventiondoes not require a delayed or long term release and instead preferablyis released in a very short time period to provide a therapeutic effectupon contact with tissue. An object of embodiments of the presentinvention is to facilitate rapid and efficient uptake of drug by targettissue during transitory device deployment at a target site.

As shown in FIG. 1, in one embodiment, the medical device is a ballooncatheter. The balloon catheter may be any suitable catheter for thedesired use, including conventional balloon catheters known to one ofordinary skill in the art. For example, balloon catheter 10 may includean expandable, inflatable balloon 12 at a distal end of the catheter 10,a handle assembly 16 at a proximal end of the catheter 10, and anelongate flexible member 14 extending between the proximal and distalends. Handle assembly 16 may connect to and/or receive one or moresuitable medical devices, such as a source of inflation media (e.g.,air, saline, or contrast media). Flexible member 14 may be a tube madeof suitable biocompatible material and having one or more lumenstherein. At least one of the lumens is configured to receive inflationmedia and pass such media to balloon 12 for its expansion. The ballooncatheter may be a rapid exchange or over-the-wire catheter and made ofany suitable biocompatible material.

In one embodiment, the present invention provides a medical device fordelivering a therapeutic agent to a tissue. The device includes a layerapplied to an exterior surface of the medical device, such as a ballooncatheter or stent, for example. The layer includes a therapeutic agentand an additive. For example, as shown in the embodiment depicted inFIG. 2A, the balloon 12 is coated with a layer 20 that includes atherapeutic agent and an additive. In some embodiments, the layerconsists essentially of a therapeutic agent and an additive, i.e., thelayer includes only the therapeutic agent and the additive, without anyother materially significant components. In some embodiments, the devicemay optionally include an adherent layer. For example, as shown in theembodiment depicted in FIG. 2B, the balloon 12 is coated with anadherent layer 22. A layer 24 that includes a therapeutic agent and anadditive is overlying the adherent layer. The adherent layer, which is aseparate layer underlying the drug coating layer, improves the adherenceof the drug coating layer to the exterior surface of the medical deviceand protects coating integrity. For example, if drug and additive differin their adherence to the medical device, the adherent layer may preventdifferential loss of components and maintain drug-to-additive ratio inthe coating during transit to a target site for therapeuticintervention. Furthermore, the adherent layer may function to facilitaterapid release of coating layer components off the device surface uponcontact with tissues at the target site.

In one embodiment, the concentration density of the at least onetherapeutic agent applied to the surface of the medical device is fromabout 1 to 20 μg/mm², or more preferably from about 2 to 6 μg/mm². Theratio by weight of the additive to the therapeutic agent in the layer isfrom about 0.05 to 100, for example, from about 0.1 to 5, from 0.5 to 2,and further for example, from about 0.8 to 1.2

In other embodiments, the layer may include a therapeutic agent and morethan one additive. For example, one additive may serve to improveballoon adhesion of another additive or additives that are superior atpromoting tissue uptake of drug.

In other embodiments, the layer may include at least one therapeuticagent, at least one additive, and at least one polymer carrier forcoating of a medical device such as a stent or a balloon. Thetherapeutic agent is not encapsulated in polymer particles. The additivein the layer improves compatibility of the drug and polymer carrier. Itreduces the size or eliminates drug crystal particles in the polymermatrix of the coating. The uniform drug distribution in the coatingimproves clinical outcomes by more uniformly delivering drug to targettissues.

In another embodiment, the device comprises two layers applied to anexterior surface of the medical device, and particularly a ballooncatheter, for example. The first layer comprises a therapeutic agent.The first layer may optionally comprise an additive or additives. Thesecond layer comprises an additive or additives. The second layer mayoptionally include at least a therapeutic agent. When the first andsecond layers both contain a therapeutic agent, the content of thetherapeutic agent in the second layer is lower than the content of thetherapeutic agent in the first layer. In one embodiment, the secondlayer is overlying the first layer. In this arrangement, the secondlayer can prevent drug loss during deployment of the medical device intobody passageways, for example, as a balloon catheter traverses thetortuous anatomy to a tissue site in the vasculature.

In another embodiment, the device comprises two layers applied to anexterior surface of the medical device, and particularly a ballooncatheter, for example. The first layer comprises a therapeutic agent.The first layer may optionally comprise an additive or additives. Thesecond layer comprises an additive or additives. The second layer mayoptionally include at least a therapeutic agent. When the first andsecond layers both contain a therapeutic agent, the content of thetherapeutic agent in the first layer is lower than the content of thetherapeutic agent in the second layer. In one embodiment, the secondlayer is overlying the first layer. This arrangement is useful, forexample, in the case of a therapeutic agent that adheres too tightly tothe balloon surface to rapidly elute off the balloon when inflated atthe target site. In this arrangement, the first layer functions tofacilitate rapid release of the bulk of drug, which is in the secondlayer, off the surface of the device while it is inflated at the targetsite of therapeutic intervention.

In other embodiments, two or more therapeutic agents are used incombination in the drug-additive layer.

In a further embodiment, the device having a two layer coating mayoptionally include an adherent layer. The adherent layer does notcontain a therapeutic agent. For example, as shown in the embodimentdepicted in FIG. 2C, the balloon 12 is coated with an adherent layer 22.A first layer 26 that comprises a therapeutic agent and optionally anadditive or additives is overlying the adherent layer 22. A second layer28 that comprises an additive and optionally a therapeutic agent isoverlying the first layer 26. The adherent layer improves the adherenceof the first layer to the exterior surface of the medical device andprotects the integrity of the first layer. For example, if drug andadditive or additives in the first layer differ in their strength ofadherence to the medical device, the adherent layer may preventdifferential loss of components and maintain drug-to-additive andadditive-to-additive ratio in the first and second layers during transitto a target site for therapeutic intervention. Furthermore, the adherentlayer may function to facilitate rapid elution of coating layer off thedevice surface upon contact with tissues at the target site. In oneembodiment, the first layer, the second layer, and the adherent layereach contain an additive.

Optionally, post-treatment with dimethylsulfoxide (DMSO) or othersolvent may be advantageous since DMSO may further enhance penetrationand absorption of drug into tissue. DMSO displaces water from the lipidhead groups and protein domains of the membrane lipid bilayer of targetcells to indirectly loosen the lipid structure, accelerating drugabsorption and penetration.

In a further embodiment, the present invention relates to apharmaceutical composition for treating a diseased body lumen orcavities after surgical or interventional procedures (PTCA, PTA, stentplacement, excision of diseased tissue such as cancer, and relieving ortreating stenosis), wherein the pharmaceutical composition comprises atherapeutic agent and an additive, wherein the additive comprises ahydrophilic part and a hydrophobic part, and wherein the therapeuticagent is not enclosed in micelles or encapsulated in polymer particles.

In another embodiment, a method of preventing complications orrecurrence of disease (such as cancer or restenosis) after a surgical orinterventional procedure such as PTCA, PTA, stent deployment, stenosisor plaque removal by debulking, atherectomy, or laser procedures, thepharmaceutical composition is locally delivered at or near the site ofintervention by means of a coated medical device (such as a drug-coatedballoon), or by spray, by injection, or by deposition. For example, thepharmaceutical composition may be delivered by spray, injection, balloonor other method of deposition, into cavities created by surgical removalof cancer tissue in order to reduce the risk of recurrence. As anotherexample, a method for delivering the pharmaceutical compositioncomprises inserting a medical device (such as guide catheter or a druginfusion catheter) into the blood to inject the pharmaceuticalcomposition after a vascular intervention such as PTCA, PTA, or stentplacement to prevent restenosis, wherein the pharmaceutical compositioncomprises a therapeutic agent and an additive, wherein the additivecomprises a hydrophilic part and a hydrophobic part, and wherein thetherapeutic agent is not enclosed in micelles or encapsulated in polymerparticles.

Additive

The additive of the present invention has two parts. One part ishydrophilic and the other part is hydrophobic or lipophilic. Thehydrophobic or lipophilic part of the additive may bind the lipophilicdrug, such as rapamycin or paclitaxel. The hydrophilic portionaccelerates diffusion and increases permeation of the drug into tissue.It may facilitate rapid movement of drug off the medical device duringdeployment and into interstitial space and through polar head groups tothe lipid bilayer of cell membranes of target tissues.

In embodiments of the present invention, the therapeutic agent israpidly released after the medical device is brought into contact withtissue and is readily absorbed.

The additive has a lipophilic or hydrophobic part and a hydrophilicpart. The hydrophobic part may include aliphatic and aromatic organichydrocarbon compounds, such as benzene, toluene, and alkanes, amongothers. These parts are not water soluble. They may bind bothhydrophobic drug, with which they share structural similarities, andlipids of cell membranes. They have no covalently bonded iodine. Thehydrophilic part may include hydroxyl groups, amine groups, amidegroups, carbonyl groups, carboxylic acid and anhydrides, ethyl oxide,ethyl glycol, polyethylene glycol, ascorbic acid amino acid, aminoalcohol, glucose, sucrose, sorbitan, glycerol, polyalcohol, phosphates,sulfates, organic salts and their substituted molecules, among others.Multiple hydroxyl, carboxyl, or amine groups, for example, may beadvantageous since they easily displace water molecules that arehydrogen-bound to polar head groups and surface proteins of cellmembranes and may function to remove this barrier between hydrophobicdrug and cell membrane lipid. These parts can dissolve in water andpolar solvents. These additives are not oils, lipids, or polymers. Thetherapeutic agent is not enclosed in micelles or liposomes orencapsulated in polymer particles. The additive of embodiments of thepresent invention have hydrophobic and hydrophilic components to bothbind drug and facilitate its rapid movement off the medical deviceduring deployment and into target tissues.

As is well known in the art, the terms “hydrophilic” and “hydrophobic”are relative terms. To function as an additive in exemplary embodimentsof the present invention, the compound includes polar or chargedhydrophilic moieties as well as non-polar hydrophobic (lipophilic)moieties.

An empirical parameter commonly used in medicinal chemistry tocharacterize the relative hydrophilicity and hydrophobicity ofpharmaceutical compounds is the partition coefficient, P, the ratio ofconcentrations of unionized compound in the two phases of a mixture oftwo immiscible solvents, usually octanol and water, such thatP=([solute]octanol/[solute]water). Compounds with higher log Ps are morehydrophobic, while compounds with lower log Ps are more hydrophilic.Lipinski's rule suggests that pharmaceutical compounds having log P<5are typically more membrane permeable. While a compound's octanol-waterpartition coefficient P or log P is useful as a measurement of relativehydrophilicity and hydrophobicity, it is merely a rough guide that maybe useful in defining suitable additives for use in embodiments of thepresent invention.

Suitable additives that can be used in embodiments of the presentinvention include, without limitation, organic and inorganicpharmaceutical excipients, natural products and their derivatives (suchas sugars, vitamins, amino acids, peptides, proteins, fatty acids), lowmolecular weight oligomers, surfactants (anionic, cationic, non-ionic,and ionic), and mixtures thereof. The following detailed list ofadditives useful in the present invention is provided for exemplarypurposes only and is not intended to be comprehensive. Many otheradditives may be useful for purposes of the present invention.

Surfactants

The surfactant can be any surfactant suitable for use in pharmaceuticalcompositions. Such surfactants can be anionic, cationic, zwitterionic ornon-ionic. Mixtures of surfactants are also within the scope of theinvention, as are combinations of surfactant and other additives.Surfactants often have one or more long aliphatic chains such as fattyacids that may insert directly into lipid bilayers of cell membranes toform part of the lipid structure, while other components of thesurfactants loosen the lipid structure and enhance drug penetration andabsorption. The contrast agent iopromide does not have these properties.

An empirical parameter commonly used to characterize the relativehydrophilicity and hydrophobicity of surfactants is thehydrophilic-lipophilic balance (“HLB” value). Surfactants with lower HLBvalues are more hydrophobic, and have greater solubility in oils, whilesurfactants with higher HLB values are more hydrophilic, and havegreater solubility in aqueous solutions. Using HLB values as a roughguide, hydrophilic surfactants are generally considered to be thosecompounds having an HLB value greater than about 10, as well as anionic,cationic, or zwitterionic compounds for which the HLB scale is notgenerally applicable. Similarly, hydrophobic surfactants are compoundshaving an HLB value less than about 10.

It should be understood that the HLB value of a surfactant is merely arough guide generally used to enable formulation of industrial,pharmaceutical and cosmetic emulsions, for example. For many importantsurfactants, including several polyethoxylated surfactants, it has beenreported that HLB values can differ by as much as about 8 HLB units,depending upon the empirical method chosen to determine the HLB value(Schott, J. Pharm. Sciences, 79(1), 87-88 (1990)). Keeping theseinherent difficulties in mind, and using HLB values as a guide,surfactants may be identified that have suitable hydrophilicity orhydrophobicity for use in embodiments of the present invention, asdescribed herein.

PEG-Fatty Acids and PEG-Fatty Acid Mono and Diesters

Although polyethylene glycol (PEG) itself does not function as asurfactant, a variety of PEG-fatty acid esters have useful surfactantproperties. Among the PEG-fatty acid monoesters, esters of lauric acid,oleic acid, and stearic acid are most useful in embodiments of thepresent invention. Preferred hydrophilic surfactants include PEG-8laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10 laurate,PEG-10 oleate, PEG-12 laurate, PEG-12 oleate, PEG-15 oleate, PEG-20laurate and PEG-20 oleate. The HLB values are in the range of 4-20.

Polyethylene glycol fatty acid diesters are also suitable for use assurfactants in the compositions of embodiments of the present invention.Most preferred hydrophilic surfactants include PEG-20 dilaurate, PEG-20dioleate, PEG-20 distearate, PEG-32 dilaurate and PEG-32 dioleate. TheHLB values are in the range of 5-15.

In general, mixtures of surfactants are also useful in embodiments ofthe present invention, including mixtures of two or more commercialsurfactants as well as mixtures of surfactants with another additive oradditives. Several PEG-fatty acid esters are marketed commercially asmixtures or mono- and diesters.

Polyethylene Glycol Glycerol Fatty Acid Esters

Preferred hydrophilic surfactants are PEG-20 glyceryl laurate, PEG-30glyceryl laurate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, andPEG-30 glyceryl oleate.

Alcohol-Oil Transesterification Products

A large number of surfactants of different degrees of hydrophobicity orhydrophilicity can be prepared by reaction of alcohols or polyalcoholwith a variety of natural and/or hydrogenated oils. Most commonly, theoils used are castor oil or hydrogenated castor oil, or an ediblevegetable oil such as corn oil, olive oil, peanut oil, palm kernel oil,apricot kernel oil, or almond oil. Preferred alcohols include glycerol,propylene glycol, ethylene glycol, polyethylene glycol, sorbitol, andpentaerythritol. Among these alcohol-oil transesterified surfactants,preferred hydrophilic surfactants are PEG-35 castor oil (Incrocas-35),PEG-40 hydrogenated castor oil (Cremophor RH 40), PEG-25 trioleate(TAGAT® TO), PEG-60 corn glycerides (Crovol M70), PEG-60 almond oil(Crovol A70), PEG-40 palm kernel oil (Crovol PK70), PEG-50 castor oil(Emalex C-50), PEG-50 hydrogenated castor oil (Emalex HC-50), PEG-8caprylic/capric glycerides (Labrasol), and PEG-6 caprylic/capricglycerides (Softigen 767). Preferred hydrophobic surfactants in thisclass include PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castoroil, PEG-9 hydrogenated castor oil, PEG-6 corn oil (Labrafil® M 2125CS), PEG-6 almond oil (Labrafil® M 1966 CS), PEG-6 apricot kernel oil(Labrafil® M 1944 CS), PEG-6 olive oil (Labrafil® M 1980 CS), PEG-6peanut oil (Labrafil® M 1969 CS), PEG-6 hydrogenated palm kernel oil(Labrafil® M 2130 BS), PEG-6 palm kernel oil (Labrafil® M 2130 CS),PEG-6 triolein (Labrafil® b M 2735 CS), PEG-8 corn oil (Labrafil® WL2609 BS), PEG-20 corn glycerides (Crovol M40), and PEG-20 almondglycerides (Crovol A40).

Polyglyceryl Fatty Acids

Polyglycerol esters of fatty acids are also suitable surfactants for usein embodiments of the present invention. Among the polyglyceryl fattyacid esters, preferred hydrophobic surfactants include polyglyceryloleate (Plurol Oleique), polyglyceryl-2 dioleate (Nikkol DGDO),polyglyceryl-10 trioleate, polyglyceryl stearate, polyglyceryl laurate,polyglyceryl myristate, polyglyceryl palmitate, and polyglyceryllinoleate. Preferred hydrophilic surfactants include polyglyceryl-10laurate (Nikkol Decaglyn 1-L), polyglyceryl-10 oleate (Nikkol Decaglyn1-O), and polyglyceryl-10 mono, dioleate (Caprol® PEG 860),polyglyceryl-10 stearate, polyglyceryl-10 laurate, polyglyceryl-10myristate, polyglyceryl-10 palmitate, polyglyceryl-10 linoleate,polyglyceryl-6 stearate, polyglyceryl-6 laurate, polyglyceryl-6myristate, polyglyceryl-6 palmitate, and polyglyceryl-6 linoleate.Polyglyceryl polyricinoleates (Polymuls) are also preferred surfactants.

Propylene Glycol Fatty Acid Esters

Esters of propylene glycol and fatty acids are suitable surfactants foruse in embodiments of the present invention. In this surfactant class,preferred hydrophobic surfactants include propylene glycol monolaurate(Lauroglycol FCC), propylene glycol ricinoleate (Propymuls), propyleneglycol monooleate (Myverol P-06), propylene glycol dicaprylate/dicaprate(Captex® 200), and propylene glycol dioctanoate (Captex® 800).

Sterol and Sterol Derivatives

Sterols and derivatives of sterols are suitable surfactants for use inembodiments of the present invention. Preferred derivatives include thepolyethylene glycol derivatives. A preferred surfactant in this class isPEG-24 cholesterol ether (Solulan C-24).

Polyethylene Glycol Sorbitan Fatty Acid Esters

A variety of PEG-sorbitan fatty acid esters are available and aresuitable for use as surfactants in embodiments of the present invention.Among the PEG-sorbitan fatty acid esters, preferred surfactants includePEG-20 sorbitan monolaurate (Tween-20), PEG-20 sorbitan monopalmitate(Tween-40), PEG-20 sorbitan monostearate (Tween-60), and PEG-20 sorbitanmonooleate (Tween-80).

Polyethylene Glycol Alkyl Ethers

Ethers of polyethylene glycol and alkyl alcohols are suitablesurfactants for use in embodiments of the present invention. Preferredethers include PEG-3 oleyl ether (Volpo 3) and PEG-4 lauryl ether (Brij30).

Sugar and its Derivatives

Sugar derivatives are suitable surfactants for use in embodiments of thepresent invention. Preferred surfactants in this class include sucrosemonopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside,n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside,heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside,n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside,nonanoyl-N-methylglucamide, n-noyl-β-D-glucopyranoside,octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside, andoctyl-β-D-thioglucopyranoside.

Polyethylene Glycol Alkyl Phenols

Several PEG-alkyl phenol surfactants are available, such as PEG-10-100nonyl phenol and PEG-15-100 octyl phenol ether, Tyloxapol, octoxynol,nonoxynol, and are suitable for use in embodiments of the presentinvention.

Polyoxyethylene-Polyoxypropylene (POE-POP) Block Copolymers

The POE-POP block copolymers are a unique class of polymericsurfactants. The unique structure of the surfactants, with hydrophilicPOE and hydrophobic POP moieties in well-defined ratios and positions,provides a wide variety of surfactants suitable for use in embodimentsof the present invention. These surfactants are available under varioustrade names, including Synperonic PE series (ICI); Pluronic® series(BASF), Emkalyx, Lutrol (BASF), Supronic, Monolan, Pluracare, andPlurodac. The generic term for these polymers is “poloxamer” (CAS9003-11-6). These polymers have the formula:HO(C₂H₄O)_(a)(C₃H₆O)_(b)(C₂H₄O)_(a)Hwhere “a” and “b” denote the number of polyoxyethylene andpolyoxypropylene units, respectively.

Preferred hydrophilic surfactants of this class include Poloxamers 108,188, 217, 238, 288, 338, and 407. Preferred hydrophobic surfactants inthis class include Poloxamers 124, 182, 183, 212, 331, and 335.

Sorbitan Fatty Acid Esters

Sorbitan esters of fatty acids are suitable surfactants for use inembodiments of the present invention. Among these esters, preferredhydrophobic surfactants include sorbitan monolaurate (Arlacel 20),sorbitan monopalmitate (Span-40), sorbitan monooleate (Span-80),sorbitan monostearate.

The sorbitan monopalmitate, an amphiphilic derivative of Vitamin C(which has Vitamin C activity), can serve two important functions insolubilization systems. First, it possesses effective polar groups thatcan modulate the microenvironment. These polar groups are the samegroups that make vitamin C itself (ascorbic acid) one of the mostwater-soluble organic solid compounds available: ascorbic acid issoluble to about 30 wt/wt % in water (very close to the solubility ofsodium chloride, for example). And second, when the pH increases so asto convert a fraction of the ascorbyl palmitate to a more soluble salt,such as sodium ascorbyl palmitate.

Ionic Surfactants

Ionic surfactants, including cationic, anionic and zwitterionicsurfactants, are suitable hydrophilic surfactants for use in embodimentsof the present invention. Preferred ionic surfactants include quaternaryammonium salts, fatty acid salts and bile salts. Specifically, preferredionic surfactants include benzalkonium chloride, benzethonium chloride,cetylpyridinium chloride, docecyl trimethyl ammonium bromide, sodiumdocecylsulfates, dialkyl methylbenzyl ammonium chloride, edrophoniumchloride, domiphen bromide, dialkylesters of sodium sulfonsuccinic acid,sodium dioctyl sulfosuccinate, sodium cholate, and sodium taurocholate.These quaternary ammonium salts are preferred additives. They can bedissolved in both organic solvents (such as ethanol, acetone, andtoluene) and water. This is especially useful for medical devicecoatings because it simplifies the preparation and coating process andhas good adhesive properties. Water insoluble drugs are commonlydissolved in organic solvents.

Fat-Soluble Vitamins and Salts Thereof

Vitamins A, D, E and K in many of their various forms and provitaminforms are considered as fat-soluble vitamins and in addition to these anumber of other vitamins and vitamin sources or close relatives are alsofat-soluble and have polar groups, and relatively high octanol-waterpartition coefficients. Clearly, the general class of such compounds hasa history of safe use and high benefit to risk ratio, making them usefulas additives in embodiments of the present invention.

The following examples of fat-soluble vitamin derivatives and/or sourcesare also useful as additives: Alpha-tocopherol, beta-tocopherol,gamma-tocopherol, delta-tocopherol, tocopherol acetate, ergosterol,1-alpha-hydroxycholecal-ciferol, vitamin D2, vitamin D3, alpha-carotene,beta-carotene, gamma-carotene, vitamin A, fursultiamine,methylolriboflavin, octotiamine, prosultiamine, riboflavine, vintiamol,dihydrovitamin K1, menadiol diacetate, menadiol dibutyrate, menadioldisulfate, menadiol, vitamin K1, vitamin K1 oxide, vitamins K2, andvitamin K-S(II). Folic acid is also of this type, and although it iswater-soluble at physiological pH, it can be formulated in the free acidform. Other derivatives of fat-soluble vitamins useful in embodiments ofthe present invention may easily be obtained via well known chemicalreactions with hydrophilic molecules.

Water-Soluble Vitamins and their Amphiphilic Derivatives

Vitamins B, C, U, pantothenic acid, folic acid, and some of themenadione-related vitamins/provitamins in many of their various formsare considered water-soluble vitamins. These may also be conjugated orcomplexed with hydrophobic moieties or multivalent ions into amphiphilicforms having relatively high octanol-water partition coefficients andpolar groups. Again, such compounds can be of low toxicity and highbenefit to risk ratio, making them useful as additives in embodiments ofthe present invention. Salts of these can also be useful as additives inthe present invention. Examples of water-soluble vitamins andderivatives include, without limitation, acetiamine, benfotiamine,pantothenic acid, cetotiamine, cyclothiamine, dexpanthenol, niacinamide,nicotinic acid, pyridoxal 5-phosphate, nicotinamide ascorbate,riboflavin, riboflavin phosphate, thiamine, folic acid, menadioldiphosphate, menadione sodium bisulfite, menadoxime, vitamin B12,vitamin K5, vitamin K6, vitamin K6, and vitamin U. Also, as mentionedabove, folic acid is, over a wide pH range including physiological pH,water-soluble, as a salt.

Compounds in which an amino or other basic group is present can easilybe modified by simple acid-base reaction with a hydrophobicgroup-containing acid such as a fatty acid (especially lauric, oleic,myristic, palmitic, stearic, or 2-ethylhexanoic acid), low-solubilityamino acid, benzoic acid, salicylic acid, or an acidic fat-solublevitamin (such as riboflavin). Other compounds might be obtained byreacting such an acid with another group on the vitamin such as ahydroxyl group to form a linkage such as an ester linkage, etc.Derivatives of a water-soluble vitamin containing an acidic group can begenerated in reactions with a hydrophobic group-containing reactant suchas stearylamine or riboflavine, for example, to create a compound thatis useful in embodiments of the present invention. The linkage of apalmitate chain to vitamin C yields ascorbyl palmitate.

Amino Acids and their Salts

Alanine, arginine, asparagines, aspartic acid, cysteine, cystine,glutamic acid, glutamine, glycine, histidine, proline, isoleucine,leucine, lysine, methionine, phenylalanine, serine, threonine,tryptophan, tyrosine, valine, and their derivatives are other usefuladditives in embodiments of the invention.

Certain amino acids, in their zwitterionic form and/or in a salt formwith a monovalent or multivalent ion, have polar groups, relatively highoctanol-water partition coefficients, and are useful in embodiments ofthe present invention. In the context of the present disclosure we take“low-solubility amino acid” to mean an amino acid which has a solubilityin unbuffered water of less than about 4% (40 mg/ml). These includeCystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine,asparagine, aspartic acid, glutamic acid, and methionine.

Amino acid dimers, sugar-conjugates, and other derivatives are alsouseful. Through simple reactions well known in the art hydrophilicmolecules may be joined to hydrophobic amino acids, or hydrophobicmolecules to hydrophilic amino acids, to make additional additivesuseful in embodiments of the present invention.

Catecholamines, such as dopamine, levodopa, carbidopa, and DOPA, arealso useful as additives.

Oligopeptides, Peptides and Proteins

Oligopeptides and peptides are useful as additives, since hydrophobicand hydrophilic amino acids may be easily coupled and various sequencesof amino acids may be tested to maximally facilitate permeation oftissue by drug.

Proteins are also useful as additives in embodiments of the presentinvention. Serum albumin, for example, is a particularly preferredadditive since it is water soluble and contains significant hydrophobicparts to bind drug: paclitaxel is 89% to 98% protein-bound after humanintravenous infusion, and rapamycin is 92% protein bound, primarily(97%) to albumin. Furthermore, paclitaxel solubility in PBS increasesover 20-fold with the addition of BSA. Albumin is naturally present athigh concentrations in serum and is thus very safe for humanintravascular use.

Other useful proteins include, without limitation, other albumins,immunoglobulins, caseins, hemoglobins, lysozymes, immunoglobins,a-2-macroglobulin, fibronectins, vitronectins, firbinogens, lipases, andthe like.

Organic Acids and their Esters and Anhydrides

Examples are acetic acid and anhydride, benzoic acid and anhydride,diethylenetriaminepentaacetic acid dianhydride,ethylenediaminetetraacetic dianhydride, maleic acid and anhydride,succinic acid and anhydride, diglycolic anhydride, glutaric anhydride,ascorbic acid, citric acid, tartaric acid, lactic acid, oxalic acidaspartic acid, nicotinic acid, 2-pyrrolidone-5-carboxylic acid, and2-pyrrolidone.

These esters and anhydrides are soluble in organic solvents such asethanol, acetone, methylethylketone, ethylacetate. The water insolubledrugs can be dissolved in organic solvent with these esters andanhydrides, then coated easily on to the medical device, then hydrolyzedunder high pH conditions. The hydrolyzed anhydrides or esters are acidsor alcohols, which are water soluble and can effectively carry the drugsoff the device into the vessel walls.

Chemical Compounds with Multiple Hydroxyl, Amine, Carbonyl, Carboxyl, orEster Moieties

Examples are L-ascorbic acid and its salt, D-glucoascorbic acid and itssalt, tromethamine, glucamine, glucoheptonic acid, glucomic acid,gluconolactone, glucosamine, glutamic acid, polyglycidol, glycerols andmultiglycerols.

Preferred additives include p-isononylphenoxypolyglycidol, PEG glyceryloleate, PEG glyceryl stearate, polyglyceryl laurate, plyglyceryl oleate,polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate,plyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, polyglyceryl-10 laurate, plyglyceryl-10 oleate,polyglyceryl-10 myristate, polyglyceryl-10 palmitate, PEG sorbitanmonolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEGsorbitan stearate, octoxynol, monoxynol, tyloxapol, sucrosemonopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside,n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside,heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside,n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside,nonanoyl-N-methylglucamide, n-noyl-β-D-glucopyranoside,octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside,octyl-β-D-thioglucopyranoside; cystine, tyrosine, tryptophan, leucine,isoleucine, phenylalanine, asparagine, aspartic acid, glutamic acid, andmethionine (amino acids); cetotiamine; cyclothiamine, dexpanthenol,niacinamide, nicotinic acid and its salt, pyridoxal 5-phosphate,nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine,folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU (vitamins); albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases, benzalkonium chloride, benzethonium chloride,docecyl trimethyl ammonium bromide, sodium docecylsulfates, dialkylmethylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid, L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, glucamine, glucoheptonic acid, glucomicacid, gluconolactone, glucosamine, glutamic acid, polyglycidol,glycerols and multiglycerols (chemical compounds with multiple hydroxyl,amino, carbonyl, carboxyl, or ester moieties). Some of these additivesare both water-soluble and organic solvent-soluble. They have goodadhesive properties and adhere to the surface of polyamide medicaldevices, such as balloon catheters. They may therefore be used in boththe adherent layer and in the drug layer of embodiments of the presentinvention. The aromatic and aliphatic groups increase the solubility ofwater insoluble drugs in the coating solution, and the polar groups ofalcohols and acids accelerate drug permeation of tissue.

Other preferred additives that may be useful in embodiments of thepresent invention include riboflavin, riboflavin-phosphate sodium,Vitamin D3, folic acid (vitamin B9), vitamin 12,diethylenetriaminepentaacetic acid dianhydride,ethylenediaminetetraacetic dianhydride, maleic acid and anhydride,succinic acid and anhydride, diglycolic anhydride, glutaric anhydride,L-ascorbic acid, thiamine, nicotinamide, nicotinic acid,2-pyrrolidone-5-carboxylic acid, cystine, tyrosine, tryptophan, leucine,isoleucine, phenylalanine, asparagine, aspartic acid, glutamic acid, andmethionine.

From a structural point of view, these additives share structuralsimilarities and are compatible with water insoluble drugs (such aspaclitaxel and rapamycin). They often contain double bonds such as C═C,C═N, C═O in aromatic or aliphatic structures. These additives alsocontain amine, alcohol, ester, amide, anhydride, carboxylic acid, and/orhydroxyl groups. Compounds containing multiple hydroxyl, carboxyl, oramine groups, for example, are especially useful as additives since theyeasily displace water next to the polar head groups and surface proteinsof cell membranes and may remove this barrier to hydrophobic drugpermeability. They thereby accelerate movement of a hydrophobic drug tothe lipid layer of cell membranes, to which it has very high affinity.They may also carry or accelerate the movement of drug off the ballooninto more aqueous environments such as the interstitial space, forexample, of vascular tissues that have been injured by balloonangioplasty or stent expansion. Additives such as polyglyceryl fattyesters, ascorbic ester of fatty acids, sugar esters, alcohols and ethersof fatty acids have fatty chains that can integrate into the lipidstructure of target tissue membranes, carrying drug to lipid structures.Some of the amino acids, vitamins and organic acids have aromatic C═Ngroups as well as amino, hydroxyl, and carboxylic components to theirstructure. They have structural parts that can bind or complex withhydrophobic drug, such as paclitaxel or rapamycin, and they also havestructural parts that facilitate tissue penetration by removing barriersbetween hydrophobic drug and lipid structure of cell membranes.

For example, isononylphenylpolyglycidol (Olin-10 G and Surfactant-10G),PEG glyceryl monooleate, sorbitan monolaurate (Arlacel 20), sorbitanmonopalmitate (Span-40), sorbitan monooleate (Span-80), sorbitanmonostearate, polyglyceryl-10 oleate, polyglyceryl-10 laurate,polyglyceryl-10 palmitate, and polyglyceryl-10 stearate all have morethan four hydroxyl groups in their hydrophilic part. These hydroxylgroups have very good affinity for the vessel wall and can displacehydrogen-bound water molecules. At the same time, they have long chainsof fatty acid, alcohol, ether and ester that can both complex withhydrophobic drug and integrate into the lipid structure of the cellmembranes to form the part of the lipid structure. This deformation orloosening of the lipid membrane of target cells may further acceleratepermeation of hydrophobic drug into tissue.

For another example, L-ascorbic acid, thiamine, maleic acids,niacinamide, and 2-pyrrolidone-5-carboxylic acid all have a very highwater and ethanol solubility and a low molecular weight and small size.They may therefore penetrate tissue easily. They also have structuralcomponents including aromatic C═N, amino, hydroxyl, and carboxylicgroups. These structures have very good compatibility with paclitaxeland rapamycin and can increase the solubility of these water-insolubledrugs in water and enhance their absorption into tissues. However, theyoften have poor adhesion to the surface of medical devices. They aretherefore preferably used in combination with other additives in thedrug layer and top layer where they are useful to enhance drugabsorption. Vitamin D2 and D3 are especially useful because theythemselves have anti-restenotic effects and reduce thrombosis,especially when used in combination with paclitaxel.

In embodiments of the present invention, the additive is soluble inaqueous solvents and is soluble in organic solvents. Extremelyhydrophobic compounds that lack sufficient hydrophilic parts and areinsoluble in aqueous solvent, such as the dye Sudan Red, are not usefulas additives in these embodiments. Sudan red is also genotoxic.

In one embodiment, the concentration density of the at least onetherapeutic agent applied to the surface of the medical device is fromabout 1 to 20 μg/mm², or more preferably from about 2 to 6 μg/mm². Inone embodiment, the concentration of the at least one additive appliedto the surface of the medical device is from about 1 to 20 μg/mm². Theratio of additives to drug by weight in the coating layer in embodimentsof the present invention is about 20 to 0.05, preferably about 10 to0.5, or more preferably about 5 to 0.8.

The relative amount of the therapeutic agent and the additive in thecoating layer may vary depending on applicable circumstances. Theoptimal amount of the additive can depend upon, for example, theparticular therapeutic agent and additive selected, the critical micelleconcentration of the surface modifier if it forms micelles, thehydrophilic-lipophilic-balance (HLB) of a surfactant or an additive'sthe octonol-water partition coefficient (P), the melting point of theadditive, the water solubility of the additive and/or therapeutic agent,the surface tension of water solutions of the surface modifier, etc.

The additives are present in exemplary coating compositions ofembodiments of the present invention in amounts such that upon dilutionwith an aqueous solution, the carrier forms a clear, aqueous dispersionor emulsion or solution, containing the hydrophobic therapeutic agent inaqueous and organic solutions. When the relative amount of surfactant istoo great, the resulting dispersion is visibly “cloudy”.

The optical clarity of the aqueous dispersion can be measured usingstandard quantitative techniques for turbidity assessment. Oneconvenient procedure to measure turbidity is to measure the amount oflight of a given wavelength transmitted by the solution, using, forexample, an UV-visible spectrophotometer. Using this measure, opticalclarity corresponds to high transmittance, since cloudier solutions willscatter more of the incident radiation, resulting in lower transmittancemeasurements.

Another method of determining optical clarity and carrier diffusivitythrough the aqueous boundary layer is to quantitatively measure the sizeof the particles of which the dispersion is composed. These measurementscan be performed on commercially available particle size analyzers.

Other considerations will further inform the choice of specificproportions of different additives. These considerations include thedegree of bioacceptability of the additives and the desired dosage ofhydrophobic therapeutic agent to be provided.

Therapeutic Agent

The drugs or biologically active materials, which can be used inembodiments of the present invention, can be any therapeutic agent orsubstance. The drugs can be of various physical states, e.g., moleculardistribution, crystal forms or cluster forms. Examples of drugs that areespecially useful in embodiments of the present invention are lipophilicsubstantially water insoluble drugs, such as paclitaxel, rapamycin,daunorubicin, doxorubicin, lapachone, vitamin D2 and D3 and analoguesand derivatives thereof. These drugs are especially suitable for use ina coating on a balloon catheter used to treat tissue of the vasculature.

Other drugs that may be useful in embodiments of the present inventioninclude, without limitation, glucocorticoids (e.g., dexamethasone,betamethasone), hirudin, angiopeptin, aspirin, growth factors, antisenseagents, anti-cancer agents, anti-proliferative agents, oligonucleotides,and, more generally, anti-platelet agents, anti-coagulant agents,anti-mitotic agents, antioxidants, anti-metabolite agents,anti-chemotactic, and anti-inflammatory agents.

Also useful in embodiments of the present invention are polynucleotides,antisense, RNAi, or siRNA, for example, that inhibit inflammation and/orsmooth muscle cell or fibroblast proliferation.

Anti-platelet agents can include drugs such as aspirin and dipyridamole.Aspirin is classified as an analgesic, antipyretic, anti-inflammatoryand anti-platelet drug. Dipyridamole is a drug similar to aspirin inthat it has anti-platelet characteristics. Dipyridamole is alsoclassified as a coronary vasodilator. Anti-coagulant agents for use inembodiments of the present invention can include drugs such as heparin,protamine, hirudin and tick anticoagulant protein. Anti-oxidant agentscan include probucol. Anti-proliferative agents can include drugs suchas amlodipine and doxazosin. Anti-mitotic agents and anti-metaboliteagents that can be used in embodiments of the present invention includedrugs such as methotrexate, azathioprine, vincristine, vinblastine,5-fluorouracil, adriamycin, and mutamycin. Antibiotic agents for use inembodiments of the present invention include penicillin, cefoxitin,oxacillin, tobramycin, and gentamicin. Suitable antioxidants for use inembodiments of the present invention include probucol. Additionally,genes or nucleic acids, or portions thereof can be used as thetherapeutic agent in embodiments of the present invention. Furthermore,collagen-synthesis inhibitors, such as tranilast, can be used as atherapeutic agent in embodiments of the present invention.

Photosensitizing agents for photodynamic or radiation therapy, includingvarious porphyrin compounds such as porfimer, for example, are alsouseful as drugs in embodiments of the present invention.

Drugs for use in embodiments of the present invention also includeeverolimus, somatostatin, tacrolimus, roxithromycin, dunaimycin,ascomycin, bafilomycin, erythromycin, midecamycin, josamycin,concanamycin, clarithromycin, troleandomycin, folimycin, cerivastatin,simvastatin, lovastatin, fluvastatin, rosuvastatin, atorvastatin,pravastatin, pitavastatin, vinblastine, vincristine, vindesine,vinorelbine, etoposide, teniposide, nimustine, carmustine, lomustine,cyclophosphamide, 4-hydroxycyclophosphamide, estramustine, melphalan,ifosfamide, trofosfamide, chlorambucil, bendamustine, dacarbazine,busulfan, procarbazine, treosulfan, temozolomide, thiotepa,daunorubicin, doxorubicin, aclarubicin, epirubicin, mitoxantrone,idarubicin, bleomycin, mitomycin, dactinomycin, methotrexate,fludarabine, fludarabine-5′-dihydrogenphosphate, cladribine,mercaptopurine, thioguanine, cytarabine, fluorouracil, gemcitabine,capecitabine, docetaxel, carboplatin, cisplatin, oxaliplatin, amsacrine,irinotecan, topotecan, hydroxycarbamide, miltefosine, pentostatin,aldesleukin, tretinoin, asparaginase, pegaspargase, anastrozole,exemestane, letrozole, formestane, aminoglutethimide, adriamycin,azithromycin, spiramycin, cepharantin, smc proliferation inhibitor-2w,epothilone A and B, mitoxantrone, azathioprine, mycophenolatmofetil,c-myc-antisense, b-myc-antisense, betulinic acid, camptothecin,lapachol, beta.-lapachone, podophyllotoxin, betulin, podophyllic acid2-ethylhydrazide, molgramostim (rhuGM-CSF), peginterferon a-2b,lenograstim (r-HuG-CSF), filgrastim, macrogol, dacarbazine, basiliximab,daclizumab, selectin (cytokine antagonist), CETP inhibitor, cadherines,cytokinin inhibitors, COX-2 inhibitor, NFkB, angiopeptin, ciprofloxacin,camptothecin, fluoroblastin, monoclonal antibodies, which inhibit themuscle cell proliferation, bFGF antagonists, probucol, prostaglandins,1,11-dimethoxycanthin-6-one, 1-hydroxy-11-methoxycanthin-6-one,scopoletin, colchicine, NO donors such as pentaerythritol tetranitrateand syndnoeimines, S-nitrosoderivatives, tamoxifen, staurosporine,beta.-estradiol, a-estradiol, estriol, estrone, ethinylestradiol,fosfestrol, medroxyprogesterone, estradiol cypionates, estradiolbenzoates, tranilast, kamebakaurin and other terpenoids, which areapplied in the therapy of cancer, verapamil, tyrosine kinase inhibitors(tyrphostines), cyclosporine A, 6-a-hydroxy-paclitaxel, baccatin,taxotere and other macrocyclic oligomers of carbon suboxide (MCS) andderivatives thereof, mofebutazone, acemetacin, diclofenac, lonazolac,dapsone, o-carbamoylphenoxyacetic acid, lidocaine, ketoprofen, mefenamicacid, piroxicam, meloxicam, chloroquine phosphate, penicillamine,hydroxychloroquine, auranofin, sodium aurothiomalate, oxaceprol,celecoxib, .beta.-sitosterin, ademetionine, myrtecaine, polidocanol,nonivamide, levomenthol, benzocaine, aescin, ellipticine, D-24851(Calbiochem), colcemid, cytochalasin A-E, indanocine, nocodazole, S 100protein, bacitracin, vitronectin receptor antagonists, azelastine,guanidyl cyclase stimulator tissue inhibitor of metal proteinase-1 and-2, free nucleic acids, nucleic acids incorporated into virustransmitters, DNA and RNA fragments, plasminogen activator inhibitor-1,plasminogen activator inhibitor-2, antisense oligonucleotides, VEGFinhibitors, IGF-1, active agents from the group of antibiotics such ascefadroxil, cefazolin, cefaclor, cefotaxim, tobramycin, gentamycin,penicillins such as dicloxacillin, oxacillin, sulfonamides,metronidazol, antithrombotics such as argatroban, aspirin, abciximab,synthetic antithrombin, bivalirudin, coumadin, enoxaparin, desulphatedand N-reacetylated heparin, tissue plasminogen activator, GpIIb/IIIaplatelet membrane receptor, factor Xa inhibitor antibody, heparin,hirudin, r-hirudin, PPACK, protamin, prourokinase, streptokinase,warfarin, urokinase, vasodilators such as dipyramidole, trapidil,nitroprussides, PDGF antagonists such as triazolopyrimidine and seramin,ACE inhibitors such as captopril, cilazapril, lisinopril, enalapril,losartan, thiol protease inhibitors, prostacyclin, vapiprost, interferona, .beta and y, histamine antagonists, serotonin blockers, apoptosisinhibitors, apoptosis regulators such as p65 NF-kB or Bcl-xL antisenseoligonucleotides, halofuginone, nifedipine, tranilast, molsidomine, teapolyphenols, epicatechin gallate, epigallocatechin gallate, Boswellicacids and derivatives thereof, leflunomide, anakinra, etanercept,sulfasalazine, etoposide, dicloxacillin, tetracycline, triamcinolone,mutamycin, procainamid, retinoic acid, quinidine, disopyramide,flecamide, propafenone, sotalol, amidorone, natural and syntheticallyobtained steroids such as bryophyllin A, inotodiol, maquiroside A,ghalakinoside, mansonine, strebloside, hydrocortisone, betamethasone,dexamethasone, non-steroidal substances (NSAIDS) such as fenoprofen,ibuprofen, indomethacin, naproxen, phenylbutazone and other antiviralagents such as acyclovir, ganciclovir and zidovudine, antimycotics suchas clotrimazole, flucytosine, griseofulvin, ketoconazole, miconazole,nystatin, terbinafine, antiprozoal agents such as chloroquine,mefloquine, quinine, moreover natural terpenoids such as hippocaesculin,barringtogenol-C21-angelate, 14-dehydroagrostistachin, agroskerin,agrostistachin, 17-hydroxyagrostistachin, ovatodiolids,4,7-oxycycloanisomelic acid, baccharinoids B1, B2, B3 and B7,tubeimoside, bruceanol A, B and C, bruceantinoside C, yadanziosides Nand P, isodeoxyelephantopin, tomenphantopin A and B, coronarin A, B, Cand D, ursolic acid, hyptatic acid A, zeorin, iso-iridogermanal,maytenfoliol, effusantin A, excisanin A and B, longikaurin B,sculponeatin C, kamebaunin, leukamenin A and B,13,18-dehydro-6-a-senecioyloxychaparrin, taxamairin A and B, regenilol,triptolide, moreover cymarin, apocymarin, aristolochic acid, anopterin,hydroxyanopterin, anemonin, protoanemonin, berberine, cheliburinchloride, cictoxin, sinococuline, bombrestatin A and B, cudraisoflavoneA, curcumin, dihydronitidine, nitidine chloride,12-beta-hydroxypregnadien-3,20-dione, bilobol, ginkgol, ginkgolic acid,helenalin, indicine, indicine-N-oxide, lasiocarpine, inotodiol,glycoside 1a, podophyllotoxin, justicidin A and B, larreatin,malloterin, mallotochromanol, isobutyrylmallotochromanol, maquiroside A,marchantin A, maytansine, lycoridicin, margetine, pancratistatin,liriodenine, bisparthenolidine, oxoushinsunine, aristolactam-AII,bisparthenolidine, periplocoside A, ghalakinoside, ursolic acid,deoxypsorospermin, psychorubin, ricin A, sanguinarine, manwu wheat acid,methylsorbifolin, sphatheliachromen, stizophyllin, mansonine,strebloside, akagerine, dihydrousambarensine, hydroxyusambarine,strychnopentamine, strychnophylline, usambarine, usambarensine,berberine, liriodenine, oxoushinsunine, daphnoretin, lariciresinol,methoxylariciresinol, syringaresinol, umbelliferon, afromoson,acetylvismione B, desacetylvismione A, and vismione A and B.

A combination of drugs can also be used in embodiments of the presentinvention. Some of the combinations have additive effects because theyhave a different mechanism, such as paclitaxel and rapamycin, paclitaxeland active vitamin D, paclitaxel and lapachone, rapamycin and activevitamin D, rapamycin and lapachone. Because of the additive effects, thedose of the drug can be reduced as well. These combinations may reducecomplications from using a high dose of the drug.

Adherent Layer

The adherent layer, which is an optional layer underlying the drugcoating layer, improves the adherence of the drug coating layer to theexterior surface of the medical device and protects coating integrity.If drug and additive differ in their adherence to the medical device,the adherent layer may prevent differential loss (during transit) orelution (at the target site) of drug layer components in order tomaintain consistent drug-to-additive or drug-to-drug ratio in the druglayer and therapeutic delivery at the target site of intervention.Furthermore, the adherent layer may function to facilitate release ofcoating layer components which otherwise might adhere too strongly tothe device for elution during brief contact with tissues at the targetsite. For example, in the case where a particular drug binds the medicaldevice tightly, more hydrophilic components are incorporated into theadherent layer in order to decrease affinity of the drug to the devicesurface.

As described above, the adherent layer comprises a polymer or anadditive or mixtures of both. The polymers that are useful for formingthe adherent layer are ones that are biocompatible and avoid irritationof body tissue. Some examples of polymers that are useful for formingthe adherent layer are polymers that are biostable, such aspolyurethanes, silicones, and polyesters. Other polymers that are usefulfor forming the adherent layer include polymers that can be dissolvedand polymerized on the medical device.

Some examples of polymers that are useful in the adherent layer ofembodiments of the present invention include polyolefins,polyisobutylene, ethylene-α-olefin copolymers, acrylic polymers andcopolymers, polyvinyl chloride, polyvinyl methyl ether, polyvinylidenefluoride and polyvinylidene chloride, polyacrylonitrile, polyvinylketones, polystyrene, polyvinyl acetate, ethylene-methyl methacrylatecopolymers, acrylonitrile-styrene copolymers, ABS resins, Nylon 12 andits block copolymers, polycaprolactone, polyoxymethylenes, polyethers,epoxy resins, polyurethanes, rayon-triacetate, cellulose, celluloseacetate, cellulose butyrate, cellophane, cellulose nitrate, cellulosepropionate, cellulose ethers, carboxymethyl cellulose, chitins,polylactic acid, polyglycolic acid, polylactic acid-polyethylene oxidecopolymers, polyethylene glycol, polypropylene glycol, polyvinylalcohol, and mixtures and block copolymers thereof.

Since the medical device undergoes mechanical manipulation, i.e.,expansion and contraction, examples of polymers that are useful in theadherent layer include elastomeric polymers, such as silicones (e.g.,polysiloxanes and substituted polysiloxanes), polyurethanes,thermoplastic elastomers, ethylene vinyl acetate copolymers, polyolefinelastomers, and EPDM rubbers. Due to the elastic nature of thesepolymers, when these polymers are used, the coating better adheres tothe surface of the medical device when the device is subjected to forcesor stress.

The adherent layer may also comprise one or more of the additivespreviously described, or other components, in order to maintain theintegrity and adherence of the coating layer to the device and tofacilitate both adherence of drug and additive components during transitand rapid elution during deployment at the site of therapeuticintervention.

Top Layer

In order to further protect the integrity of the drug layer, an optionaltop layer may be applied to prevent loss of drug during transit throughtortuous anatomy to the target site.

Solvents

Solvents for the preparing of the coating layer may include, asexamples, any combination of one or more of the following: (a) water,(b) alkanes such as hexane, octane, cyclohexane, and heptane, (c)aromatic solvents such as benzene, toluene, and xylene, (d) alcoholssuch as ethanol, propanol, and isopropanol, diethylamide, ethyleneglycol monoethyl ether, Trascutol, and benzyl alcohol (e) ethers such asdioxane, dimethyl ether and tetrahydrofuran, (f) esters/acetates such asethyl acetate and isobutyl acetate, (g) ketones such as acetone,acetonitrile, diethyl ketone, and methyl ethyl ketone, and (h) mixtureof water and organic solvents such as water/ethanol, water/acetone,water/methanol, water/tetrahydrofuran.

Organic solvents, such as short-chained alcohol, dioxane,tetrahydrofuran, dimethylformamide, acetonitrile, dimethylsulfoxide,etc., are particularly useful and preferred solvents in embodiments ofthe present invention because these organic solvents generally disruptcollodial aggregates and co-solubilize all the components in the coatingsolution.

The therapeutic agent and additive or additives may be dispersed in,solubilized, or otherwise mixed in the solvent. The weight percent ofdrug and additives in the solvent may be in the range of 0.1-80% byweight, preferably 2-20% by weight.

Another embodiment of the invention relates to a method for preparing amedical device, particularly, for example, a balloon catheter or astent. First, a coating solution or suspension comprising at least onesolvent, at least one therapeutic agent, and at least one additive isprepared. In at least one embodiment, the coating solution or suspensionincludes only these three components. The content of the therapeuticagent in the coating solution can be from 0.5-50% by weight based on thetotal weight of the solution. The content of the additive in the coatingsolution can be from 1-45% by weight, 1 to 40% by weight, or from 1-15%by weight based on the total weight of the solution. The amount ofsolvent used depends on the coating process and viscosity. It willaffect the uniformity of the drug-additive coating but will beevaporated.

In other embodiments, two or more solvents, two or more therapeuticagents, and/or two or more additives may be used in the coatingsolution.

In other embodiments, a therapeutic agent, an additive and a polymericmaterial may be used in the coating solution, for example in a stentcoating. In the coating, the therapeutic agent is not encapsulated inpolymer particles.

Various techniques may be used for applying a coating solution to amedical device such as casting, spinning, spraying, dipping (immersing),ink jet printing, electrostatic techniques, and combinations of theseprocesses. Choosing an application technique principally depends on theviscosity and surface tension of the solution. In embodiments of thepresent invention, dipping and spraying are preferred because it makesit easier to control the uniformity of the thickness of the coatinglayer as well as the concentration of the therapeutic agent applied tothe medical device. Regardless of whether the coating is applied byspraying or by dipping or by another method or combination of methods,each layer is usually deposited on the medical device in multipleapplication steps in order to control the uniformity and the amount oftherapeutic substance and additive applied to the medical device.

Each applied layer is from about 0.1 microns to 15 microns in thickness.The total number of layers applied to the medical device is in a rangeof from about 2 to 50. The total thickness of the coating is from about2 to 200 microns.

As discussed above, spraying and dipping are particularly useful coatingtechniques for use in embodiments of the present invention. In aspraying technique, a coating solution or suspension of an embodiment ofthe present invention is prepared and then transferred to an applicationdevice for applying the coating solution or suspension to a ballooncatheter.

An application device that may be used is a paint jar attached to an airbrush, such as a Badger Model 150, supplied with a source of pressurizedair through a regulator (Norgren, 0-160 psi). When using such anapplication device, once the brush hose is attached to the source ofcompressed air downstream of the regulator, the air is applied. Thepressure is adjusted to approximately 15-25 psi and the nozzle conditionchecked by depressing the trigger.

Prior to spraying, both ends of the relaxed balloon are fastened to thefixture by two resilient retainers, i.e., alligator clips, and thedistance between the clips is adjusted so that the balloon remained in adeflated, folded, or an inflated or partially inflated, unfoldedcondition. The rotor is then energized and the spin speed adjusted tothe desired coating speed, about 40 rpm.

With the balloon rotating in a substantially horizontal plane, the spraynozzle is adjusted so that the distance from the nozzle to the balloonis about 1-4 inches. First, the coating solution is sprayedsubstantially horizontally with the brush being directed along theballoon from the distal end of the balloon to the proximal end and thenfrom the proximal end to the distal end in a sweeping motion at a speedsuch that one spray cycle occurred in about three balloon rotations. Theballoon is repeatedly sprayed with the coating solution, followed bydrying, until an effective amount of the drug is deposited on theballoon.

In one embodiment of the present invention, the balloon is inflated orpartially inflated, the coating solution is applied to the inflatedballoon, for example by spraying, and then the balloon is deflated andfolded before drying. Drying may be performed under vacuum.

It should be understood that this description of an application device,fixture, and spraying technique is exemplary only. Any other suitablespraying or other technique may be used for coating the medical device,particularly for coating the balloon of a balloon catheter or stentdelivery system or stent.

After the medical device is sprayed with the coating solution, thecoated balloon is subjected to a drying in which the solvent in thecoating solution is evaporated. This produces a coating matrix on theballoon containing the therapeutic agent. One example of a dryingtechnique is placing a coated balloon into an oven at approximately 20°C. or higher for approximately 24 hours. Any other suitable method ofdrying the coating solution may be used. The time and temperature mayvary with particular additives and therapeutic agents.

Optional Post Treatment

After depositing the drug-additive containing layer on the device ofcertain embodiments of the present invention, Dimethyl sulfoxide (DMSO)or other solvent may be applied, by dip or spray or other method, to thefinished surface of the coating. DMSO readily dissolves drugs and easilypenetrates membranes and may enhance tissue absorption.

It is contemplated that the medical devices of embodiments of thepresent invention have applicability for treating blockages andocclusions of any body passageways, including, among others, thevasculature, including coronary, peripheral, and cerebral vasculature,the gastrointestinal tract, including the esophagus, stomach, smallintestine, and colon, the pulmonary airways, including the trachea,bronchi, bronchioles, the sinus, the biliary tract, the urinary tract,prostate and brain passages. They are especially suited for treatingtissue of the vasculature with, for example, a balloon catheter or astent.

Yet another embodiment of the present invention relates to a method oftreating a blood vessel. The method includes inserting a medical devicecomprising a coating into a blood vessel. The coating layer comprises atherapeutic agent and an additive. In this embodiment, the medicaldevice can be configured as having at least an expandable portion. Someexamples of such devices include balloon catheters, perfusion ballooncatheters, cutting balloon catheters, scoring balloon catheters,self-expanded and balloon expanded-stents, guide catheters, guide wires,embolic protection devices, and various imaging devices.

As mentioned above, one example of a medical device that is particularlyuseful in the present invention is a coated balloon catheter. A ballooncatheter typically has a long, narrow, hollow tube tabbed with aminiature, deflated balloon. In embodiments of the present invention,the balloon is coated with a drug solution. Then, the balloon ismaneuvered through the cardiovascular system to the site of a blockage,occlusion, or other tissue requiring a therapeutic agent. Once in theproper position, the balloon is inflated and contacts the walls of theblood vessel and/or a blockage or occlusion. It is an object ofembodiments of the present invention to rapidly deliver drug to andfacilitate absorption by target tissue. It is advantageous toefficiently deliver drug to tissue in as brief a period of time aspossible while the device is deployed at the target site. Thetherapeutic agent is released into such tissue, for example the vesselwalls, in about 0.1 to 30 minutes, for example, or preferably about 0.1to 10 minutes, or more preferably about 0.2 to 2 minutes, or mostpreferably, about 0.1 to 1 minutes, of balloon inflation time pressingthe drug coating into contact with diseased vascular tissue.

Given that a therapeutically effective amount of the drug can bedelivered by embodiments of the present invention into, for example, thearterial wall, in some cases the need for a stent may be eliminated,obviating the complications of fracture and thrombosis associatedtherewith.

Should placement of a stent still be desired, a particularly preferreduse for embodiments of the present invention is to crimp a stent, suchas a bare metal stent (BMS), for example, over the drug coated balloondescribed in embodiments herein. When the balloon is inflated to deploythe stent at the site of diseased vasculature, an effective amount ofdrug is delivered into the arterial wall to prevent or decrease theseverity of restenosis or other complications. Alternatively, the stentand balloon may be coated together, or the stent may be coated and thencrimped on a balloon.

Further, the balloon catheter may be used to treat vasculartissue/disease alone or in combination with other methods for treatingthe vasculature, for example, photodynamic therapy or atherectomy.Atherectomy is a procedure to remove plaque from arteries. Specifically,atherectomy removes plaque from peripheral and coronary arteries. Themedical device used for peripheral or coronary atherectomy may be alaser catheter or a rotablator or a direct atherectomy device on the endof a catheter. The catheter is inserted into the body and advancedthrough an artery to the area of narrowing. After the atherectomy hasremoved some of the plaque, balloon angioplasty using the coated balloonof embodiments of the present invention may be performed. In addition,stenting may be performed thereafter, or simultaneous with expansion ofthe coated balloon as described above. Photodynamic therapy is aprocedure where light or irradiated energy is used to kill target cellsin a patient. A light-activated photosensitizing drug may be deliveredto specific areas of tissue by embodiments of the present invention. Atargeted light or radiation source selectively activates the drug toproduce a cytotoxic response and mediate a therapeuticanti-proliferative effect.

In some of the embodiments of drug-containing coatings and layersaccording to the present invention, however, the coating or layer doesnot include polymers, oils, or lipids. And, furthermore, the therapeuticagent is not encapsulated in polymer particles, micelles, or liposomes.As described above, such formulations have significant disadvantages andcan inhibit the intended efficient, rapid release and tissue penetrationof the agent, especially in the environment of diseased tissue of thevasculature.

Although various embodiments are specifically illustrated and describedherein, it will be appreciated that modifications and variations of thepresent invention are covered by the above teachings and are within thepurview of the appended claims without departing from the spirit andintended scope of the invention.

Other than the operating examples, or where otherwise indicated, allnumbers expressing quantities of components in a layer, reactionconditions, and so forth used in the specification and claims are to beunderstood as being modified in all instances by the term “about.”Accordingly, unless otherwise indicated to the contrary, the numericalparameters set forth in this specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained by the present disclosure.

Preparation

The medical device and the coating layers of embodiments of the presentinvention can be made according to various methods. For example, thecoating solution can be prepared by dispersing, dissolving, diffusing,or otherwise mixing all the ingredients, such as a therapeutic agent, anadditive, and a solvent, simultaneously together. Also, the coatingsolution can be prepared by sequentially adding each component based onsolubility or any other parameters. For example, the coating solutioncan be prepared by first adding the therapeutic agent to the solvent andthen adding the additive. Alternatively, the additive can be added tothe solvent first and then the therapeutic agent can be later added. Ifthe solvent used does not sufficiently dissolve the drug, it ispreferable to first add the additive to the solvent, then the drug,since the additive will increase drug solubility in the solvent.

EXAMPLES

The following examples include embodiments of medical devices andcoating layers within the scope of the present invention. While thefollowing examples are considered to embody the present invention, theexamples should not be interpreted as limitations upon the presentinvention.

Example 1 Preparation of Coating Solutions

Solution 1—50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml acetone (orethanol), 25-100 mg ascorbyl palmitate, 25-100 mg L-ascorbic acid and0.5 ml ethanol are mixed.

Solution 2—50-150 mg (0.05-0.16 mmole) rapamycin, 2-6 ml acetone (orethanol), 50-200 mg polyglyceryl-10 oleate and 0.5 ml ethanol are mixed.

Solution 3—50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml acetone (orethanol), 50-200 mg octoxynol-9 and 0.5 ml ethanol are mixed.

Solution 4—50-150 mg (0.05-0.16 mmole) rapamycin, 2-6 ml acetone (orethanol), 50-200 mg p-isononylphenoxypolyglycidol and 0.5 ml ethanol aremixed.

Solution 5—50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml acetone (orethanol), 50-200 mg Tyloxapol and 0.5 ml ethanol are mixed.

Solution 6—50-150 mg (0.05-0.16 mmole) rapamycin in 2-6 ml acetone (orethanol), 50-150 mg L-ascorbic acid in 1 ml water or ethanol, both, thenare mixed.

Solution 7—50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml acetone (orethanol), 50-150 mg niacinamide in 1 ml water or ethanol, and both aremixed.

Solution 8—50-150 mg (0.05-0.16 mmole) rapamycin, 2-6 ml acetone (orethanol), 50-200 mg nicotinic acid in 1 ml water or ethanol and both aremixed.

Solution 9—50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml ethanol (oracetone), 150 mg thiamine hydrochloride in 1 ml water, and 0.5 ml bothare mixed.

Solution 10—50-150 mg (0.05-0.16 mmole) rapamycin, 2-6 ml acetone orethanol, 150 mg 2-pyrrolidone-5-carboxylic acid in 1 ml water orethanol, and both are mixed.

Solution 11—50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml acetone (orethanol), 75 mg p-isononylphenoxypolyglycidol, 75 mg niacinamide in 1 mlwater or ethanol, and 0.5 ml ethanol are mixed.

Solution 12—50-150 mg (0.05-0.16 mmole) rapamycin, 2-6 ml acetone (orethanol), 75 mg Octoxynol-9, 75 mg thiamine hydrochloride in 1 ml wateror ethanol, and 0.5 ml ethanol are mixed.

Solution 13—50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml acetone (orethanol), 75 mg p-isononylphenoxypolyglycidol, 75 mg2-pyrrolidone-5-carboxylic acid in 1 ml water or ethanol, and 0.5 mlethanol are mixed.

Solution 14—50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml acetone (orethanol), 75 mg p-isononylphenoxypolyglycidol, 75 mg nicotinic acid in 1ml water or ethanol, and 0.5 ml ethanol are mixed.

Solution 15 50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml acetone (orethanol), 75 mg p-isononylphenoxypolyglycidol, 75 mg L-ascorbic acid in1 ml water or ethanol, and 0.5 ml ethanol are mixed.

Solution 16 50-150 mg (0.06-0.18 mmole) paclitaxel is dissolved in 5-10ml methylene chloride. The solution is added to 30 ml of human serumalbumin solution (5% w/v). The solution is then homogenized for 5minutes at low speed to form an emulsion. The emulsion is then sonicatedat 40 kHz at 50-90% power at 0 to 5 degrees C. for 1 to 5 min.

Solution 17—50-150 mg (0.05-0.16 mmole) rapamycin is dissolved in 5-10ml methylene chloride and 10-30 mg p-isononylphenoxypolyglycidol. Thesolution is added to 30 ml of human serum albumin solution (5% w/v). Thesolution is then homogenized for 5 minutes at low speed to form anemulsion. The emulsion is then sonicated at 40 kHz at 50-90% power at 0to 5 degrees C. for 1 to 5 min.

Example 2

PTCA balloon catheters (3 mm in diameter and 20 mm in length) are foldedwith three wings under vacuum. The folded balloon under vacuum issprayed or dipped in a solution (1-17) in example 1. The folded balloonis then dried, sprayed or dipped again, dried again, and sprayed ordipped again until sufficient amount of drug on the balloon (3 microgramper square mm) is obtained. The coated folded balloon is then rewrappedand sterilized for animal testing.

Example 3

5 PTCA balloon catheters (3 mm in diameter and 20 mm in length) arefolded with three wings under vacuum. The folded balloon under vacuum issprayed or dipped in a solution (1-5) in example 1. The folded balloonis then dried, sprayed or dipped again in a solution (6-10), dried, andsprayed or dipped again until sufficient amount of drug on the balloon(3 microgram per square mm) is obtained. The coated folded balloon isthen rewrapped and sterilized for animal testing.

Example 4

5 PTCA balloon catheters crimped with bare metal coronary stent (3 mm indiameter and 20 mm in length) are sprayed or dipped in a solution (1-5)in example 1. The stent delivery system is then dried, sprayed or dippedagain in a solution (6-10), dried and sprayed or dipped again untilsufficient amount of drug on the stent and balloon (3 microgram persquare mm) is obtained. The coated folded stent delivery system is thensterilized for animal testing.

Example 5

Drug coated balloon catheters and uncoated balloon catheters (ascontrol) are inserted into coronary arteries in pigs. The balloon isover dilated (1:1.2), and the inflated balloon is held in the vessel for60 seconds to release drug, then deflated and withdraw from the pig. Theanimals are angiographed after 3 days, 31 days, 3 months, 6 months, 9months and 12 months. The amount of drug in the artery tissues of thesacrificed animal is measured after 60 minutes, 3 days, 31 days, 3months, 6 months, 9 months and 12 months.

Example 6

5 coronary stents (3 mm in diameter and 18 mm in length) are spray ordip coated with the solution (1-17) in example 1. The stents are thendried, sprayed or dipped again, and dried again until a sufficientamount of drug on the stent (3 microgram per square mm) is obtained. Thecoated stent is then crimped on PTCA balloon catheters (3 mm indiameters and 20 mm in length). The coated stents with balloon cathetersare then sterilized for animal testing.

Example 7

The drug coated stent and uncoated stent (as control) are inserted intocoronary arteries in pigs, then the balloon is over dilated (1:1.2). Thestent is implanted and drug released, and the balloon is deflated andwithdraw from the pig. The animals are then angiographed after 5, 30, 60minutes, 3 days, 31 days, 3 months, 6 months, 9 months and 12 months.The amount of drug in the artery tissues of the sacrificed animal ismeasured 60 minutes, 1 day, 3 days, 31 days, 3 months, 6 months, 9months and 12 months.

Example 8

5 PTCA balloon catheters are sprayed or dipped in the solution (1-17) inexample 1, dried, and sprayed or dipped and dried again until sufficientamount of drug on balloon is obtained (3 microgram per square mm) isobtained. A bare metal coronary stent (3 mm in diameter and 20 mm inlength) is crimped on each coated balloon. The coated balloons withcrimped bare metal stents are then wrapped and sterilized for animaltest.

Example 9

5 PTCA balloon catheters are sprayed or dipped in a solution (1-5) inexample 1, dried, and sprayed or dipped again in a solution (6-10).Balloons are then dried and sprayed or dipped again until sufficientamount of drug on the balloon (3 microgram per square mm) is obtained. Abare metal coronary stent (3 mm in diameter and 20 mm in length) iscrimped on each coated balloon. The coated balloons with crimped baremetal stents are then wrapped and sterilized for animal test.

Example 10

The drug coated balloon-expandable bare metal stent of Example 8 and 9and plain balloon-expandable bare metal stent (as control) are insertedinto coronary arteries in pigs, and the balloon is over dilated (1:1.2).Stent is implanted, and the balloon is held inflated for 60 seconds torelease drug, and the balloon is deflated and withdraw from the pig. Theanimals are then angiographed after 5, 30, 60 minutes, 3 days, 31 days,3 months, 6 months, 9 months and 12 months. The amount of drug in theartery tissues of the sacrificed animal is measured after 60 minutes, 1day, 3 days, 31 days, 3 months, 6 months, 9 months and 12 months.

Example 11

150 mg (0.18 mmole) paclitaxel, 5 ml acetone (or ethylacetate or methylethyl ketone), 150 mg acetic anhydride or maleic anhydride or diglycolicanhydride and 0.5 ml ethanol are mixed, then stirred until a solution isobtained. 5 PTCA balloon catheters are sprayed or dipped in thesolution, dried, and sprayed or dipped again until sufficient amount ofdrug on the balloon (3 microgram per square mm) is obtained. The coatedballoon is then treated under high pH (range pH 8-11.5) conditions tohydrolyze the anhydride. This can be confirmed by IR method. Thehydrophilicity of the coating is now increased. The coated balloons arethen sterilized for animal test.

Example 12

The drug coated balloon catheters and uncoated balloon catheters (ascontrol) are inserted via a bronchoscope into the pulmonary airway inpigs. The balloon is dilated, and the inflated balloon is held expandedin the lumen for 60 seconds to release drug. The balloon is deflated andwithdrawn from the pig. The animals are then examined bronchoscopicallyand tissues samples are taken for pathology and quantification of druguptake after 3 days, 31 days, 3 months, 6 months, 9 months and 12months.

Example 13

The uncoated stent delivery catheters are inserted into the vascularlumen in pigs. The balloon is dilated, the stent is deployed and thedeflated balloon is the withdrawn. The pharmaceutical solution 1-15 ofexample 1 (10-100 ml) is injected (about 5-15 mg drug per pig) at thesite of stent implantation. The drug is then absorbed by injuriedtissue. The animals are then examined and tissues samples are taken forpathology.

Example 14

The diseased tissue (breast cancer or atheroma or stenosis) is removedsurgically from a human body. The pharmaceutical solution 1-15 ofexample 1 (10-100 ml) is then injected into or onto the surgicalcavities created by the surgical intervention (about 5-20 mg drug). Thelocal drug delivery includes injection by long needle, guide catheters,introducer shealth, drug infusion tube and other drug deliverycatheters. The drug is then absorbed by tissue at the target site.

What is claimed is:
 1. A method for treating a blood vessel, the methodcomprising: inserting a balloon catheter into the blood vessel, theballoon catheter comprising: an inflatable polyamide balloon; and acoating layer that adheres to an exterior surface of the inflatablepolyamide balloon, wherein: the coating layer comprises a hydrophobictherapeutic agent and a water-soluble additive; the hydrophobictherapeutic agent is selected from the group consisting of paclitaxel,rapamycin, everolimus, docetaxel, and combinations thereof; thehydrophobic therapeutic agent is not enclosed in micelles or liposomesand is not encapsulated in polymer particles; the water-soluble additivecomprises a PEG fatty ester selected from the group consisting of PEGlaurates, PEG oleates, PEG stearates, PEG glyceryl laurates, PEGglyceryl oleates, PEG glyceryl stearates, PEG sorbitan monolaurates, PEGsorbitan monooleates, PEG sorbitan stearates, PEG sorbitan laurates, PEGsorbitan oleates, and PEG sorbitan palmitates; the ratio by weight ofthe at least one additive to the therapeutic agent in the coating layeris from about 0.05 to 100; inflating the balloon catheter to press thecoating layer into contact with walls of the blood vessel during aballoon inflation time of 2 minutes or less; releasing a therapeuticallyeffective amount of the therapeutic agent from the inflated ballooncatheter to the walls of the blood vessel during the balloon inflationtime; deflating the inflated balloon catheter in the blood vessel at theend of the balloon inflation time; and withdrawing the deflated ballooncatheter from the blood vessel.
 2. The method of claim 1, wherein thewater-soluble additive is selected from a group consisting of PEG-8laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10 laurate,PEG-10 oleate, PEG-12 laurate, PEG-12 oleate, PEG-15 oleate, PEG-20laurate, PEG-20 oleate, PEG-20 dilaurate, PEG-20 dioleate, PEG-20distearate, PEG-32 dilaurate and PEG-32 dioleate, and PEG-20 sorbitanmonolaurate, PEG-20 sorbitan monopalmitate, PEG-20 sorbitanmonostearate, and PEG-20 sorbitan monooleate.
 3. The method of claim 1,wherein the water-soluble additive is selected from the group consistingof PEG-20 sorbitan monolaurate, PEG-20 sorbitan monopalmitate, PEG-20sorbitan monostearate, and PEG-20 sorbitan monooleate.
 4. The method ofclaim 1, wherein the water-soluble additive is selected from the groupconsisting of PEG-20 sorbitan monolaurate and PEG-20 sorbitanmonooleate.
 5. The method of claim 1, wherein the concentration of thetherapeutic agent in the coating layer is from 1 μg/mm² to 20 μg/mm². 6.The method of claim 1, wherein the concentration of the water-solubleadditive in the coating layer is from 1 μg/mm² to 10 μg/mm².
 7. Themethod of claim 1, wherein the ratio by weight of the water-solubleadditive to the therapeutic agent in the coating layer is from about 0.5to
 2. 8. The method of claim 1, wherein the balloon catheter is aperfusion balloon catheter, a cutting balloon catheter, or a scoringballoon catheter.
 9. The method of claim 1, wherein the balloon catheterfurther comprises a dimethylsulfoxide solvent layer overlying thecoating layer.
 10. The method of claim 1, wherein the hydrophobictherapeutic agent is selected from the group consisting of paclitaxeland rapamycin.
 11. The method of claim 1, wherein the hydrophobictherapeutic agent is paclitaxel.
 12. The method of claim 1, wherein: thehydrophobic therapeutic agent is paclitaxel; and the water-solubleadditive is selected from the group consisting of PEG-20 sorbitanmonolaurate and PEG-20 sorbitan monooleate.
 13. The method of claim 1,wherein the coating layer does not include an iodine covalent bondedcontrast agent, oil, or a lipid.
 14. The method of claim 1, wherein thecoating layer does not include a polymer.
 15. The method of claim 1,further comprising: crimping a stent over the coated balloon of theballoon catheter before inserting the balloon catheter into the bodypassage.
 16. A method for treating a blood vessel, the methodcomprising: removing plaque from a target site of the blood vessel;inserting a balloon catheter into the blood vessel to the target site,the balloon catheter comprising: an inflatable polyamide balloon; and acoating layer that adheres to an exterior surface of the inflatablepolyamide balloon, wherein: the coating layer comprises a hydrophobictherapeutic agent and at least one water-soluble additive; thehydrophobic therapeutic agent is selected from the group consisting ofpaclitaxel, rapamycin, everolimus, docetaxel, and combinations thereof;the hydrophobic therapeutic agent is not enclosed in micelles orliposomes and is not encapsulated in polymer particles; the at least onewater-soluble additive comprises a PEG fatty ester selected from thegroup consisting of PEG laurates, PEG oleates, PEG stearates, PEGglyceryl laurates, PEG glyceryl oleates, PEG glyceryl stearates, PEGsorbitan monolaurates, PEG sorbitan monooleates, PEG sorbitan stearates,PEG sorbitan laurates, PEG sorbitan oleates, and PEG sorbitanpalmitates; the ratio by weight of the at least one additive to thetherapeutic agent in the coating layer is from about 0.05 to 100;inflating the balloon catheter to press the coating layer into contactwith walls of the blood vessel during a balloon inflation time of 2minutes or less; releasing a therapeutically effective amount of thetherapeutic agent from the inflated balloon catheter to the walls of theblood vessel during the balloon inflation time; deflating the inflatedballoon catheter in the blood vessel at the end of the balloon inflationtime; and withdrawing the deflated balloon catheter from the bloodvessel.
 17. The method of claim 6, wherein removing plaque from thetarget site of the blood vessel comprises removing the plaque by one ofa debulking catheter, a laser atherectomy, a directing atherectomy, or arotational atherectomy.
 18. The method of claim 16, wherein the ballooncatheter is inserted into the blood vessel after the plaque is removed.19. The method of claim 16, further comprising: crimping a stent overthe coated balloon of the balloon catheter before inserting the ballooncatheter into the blood vessel.
 20. The method of claim 16, wherein thewater-soluble additive is selected from the group consisting of PEG-20sorbitan monolaurate and PEG-20 sorbitan monooleate.
 21. The method ofclaim 16, wherein the concentration of the therapeutic agent in thecoating layer is from 1 μg/mm² to 20 μg/mm².
 22. The method of claim 16,wherein the ratio by weight of the water-soluble additive to thetherapeutic agent in the coating layer is from about 0.1 to
 5. 23. Themethod of claim 16, wherein the balloon catheter is a perfusion ballooncatheter, a cutting balloon catheter, or a scoring balloon catheter. 24.The method of claim 16, wherein the hydrophobic therapeutic agent isselected from the group consisting of paclitaxel, rapamycin, andcombinations thereof.
 25. The method of claim 16, wherein thehydrophobic therapeutic agent is paclitaxel.
 26. The method of claim 16,wherein: the hydrophobic therapeutic agent is paclitaxel; and thewater-soluble additive is selected from the group consisting of PEG-20sorbitan monolaurate and PEG-20 sorbitan monooleate.
 27. The method ofclaim 16, wherein the coating layer does not include an iodine covalentbonded contrast agent, oil, or a lipid.
 28. The method of claim 16,wherein the coating layer does not include a polymer.
 29. A method fortreating tissue in a body passage of a body, the method comprising:inserting a balloon catheter into the body passage, the balloon cathetercomprising: an inflatable polyamide balloon; and a coating layer thatadheres to an exterior surface of the inflatable polyamide balloon,wherein: the coating layer comprises a hydrophobic therapeutic agent andat least one water-soluble additive; the hydrophobic therapeutic agentis selected from the group consisting of paclitaxel, rapamycin,everolimus, docetaxel, and combinations thereof; the hydrophobictherapeutic agent is not enclosed in micelles or liposomes and is notencapsulated in polymer particles; the at least one water-solubleadditive comprises a PEG fatty ester selected from the group consistingof PEG laurates, PEG oleates, PEG stearates, PEG glyceryl laurates, PEGglyceryl oleates, PEG glyceryl stearates, PEG sorbitan monolaurates, PEGsorbitan monooleates, PEG sorbitan stearates, PEG sorbitan laurates, PEGsorbitan oleates, and PEG sorbitan palmitates; the ratio by weight ofthe at least one additive to the therapeutic agent in the coating layeris from about 0.05 to 100; inflating the balloon catheter to contact thecoating layer with the tissue in the body passage during a ballooninflation time of 2 minutes or less; releasing a therapeuticallyeffective amount of the therapeutic agent from the inflated ballooncatheter to the tissue in the body passage during the balloon inflationtime; deflating the inflated balloon catheter in the body passage at theend of the balloon inflation time; and withdrawing the deflated ballooncatheter from the body passage.
 30. The method of claim 29, wherein thetissue is selected from the group consisting of coronary vasculaturetissue, peripheral vasculature tissue, cerebral vasculature tissue,esophageal tissue, pulmonary airway tissue, sinus tissue, trachealtissue, colon tissue, biliary tract tissue, urinary tract tissue,prostate tissue, and brain passage tissue.
 31. The method of claim 29,further comprising: crimping a stent over the coated balloon of theballoon catheter before inserting the balloon catheter into the bodypassage.
 32. The method of claim 29, wherein the water-soluble additiveis selected from the group consisting of PEG-20 sorbitan monolaurate,PEG-20 sorbitan monopalmitate, PEG-20 sorbitan monostearate, and PEG-20sorbitan monooleate.
 33. The method of claim 29, wherein thewater-soluble additive is selected from the group consisting of PEG-20sorbitan monolaurate and PEG-20 sorbitan monooleate.
 34. The method ofclaim 29, further comprising a dimethylsulfoxide solvent layer overlyingthe coating layer.
 35. The method of claim 29, wherein the hydrophobictherapeutic agent is selected from the group consisting of paclitaxeland rapamycin.
 36. The method of claim 29, wherein: the hydrophobictherapeutic agent is paclitaxel; and the water-soluble additive isselected from the group consisting of PEG-20 sorbitan monolaurate andPEG-20 sorbitan monooleate.